DRUG DISPOSITION
Clin. Pharmacokinel. 21 (2): 110· 128, 1991 0312.5963/ 91 / 0008·0110/ $09.50/0 © Adis International Limited. All rights reserved. CPK1038
Pharmacokinetics of Rectal Drug Administration, Part II Clinical Applications of Peripherally Acting Drugs, and Conclusions Ewoud J. van Hoogdalem . Albertus G, de Boer and Douwe D, Breimer Brocades Pharma B.Y., Delft, and Center for Biopharmaceutical Sciences, Division of Pharmacology, Sylvius Laboratories, University of Leiden, Leiden, The Netherlands
Contents 110 110 114 1/6 II" 118 119 /10 112 123
Summary
Summary 3.5 Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs 3.6 Antibacterial Agents 3.7 Xanthine Drugs 3.8 Anticancer Agents 3.9 Drugs in Inflammatory Bowel Disease 3. 10 Cardiovascular Active Drugs 3.11 Miscellaneous 4. Enhancement of Rectal Drug Absorption 5. Conclusions
Part I of this article, which appeared in the previous issue of the Journal, covered general considerations, the physiology of the rectum, spreading of drugs into the colon, rectal absorption, partial avoidance of first-pass elimination, rate-controlled rectal delivery of drugs, irritation of the rectal mucosa and clinical applications of rectal administration, and discussed centrally acting drugs. In Part II, this discussion is extended to drugs which act peripherally and to methods of enhancing rectal drug absorption. The overall summary appeared in Part I.
3.5 Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs Rectal administration of non-narcotic analgesics may be indicated in various circumstances, e,g. in patients with nausea or vomiting or who are otherwise unable to take oral medication (infants), and also to avoid local irritation of the upper gastrointestinal tract. Therefore, the feasibility of rectal administration has been the topic of various studies with drugs of this class.
3.5.1 Paracetamol Rectally administered aqueous suspensions of paracetamol resulted in bioavailabilities which were comparable with those observed after oral administration, with the extent of absorption increasing with the volume of the suspension (Moolenaar et al. 1979). The rectal bioavailability of a 20ml suspension of paracetamol Ig was 91 %, relative to oral delivery, and similar results were obtained in children after rectal administration of paracetamol 20 mg/kg as an aqueous solution (Gaudreault et al.
Pharmacokinetics of Drugs Administered Rectally
1988). The latter treatment was not considered to be effective in preventing postoperative pain in children undergoing adenotonsillectomy. Concerning absorption from suppositories, the bioavailability from a fatty base with 0.8% of polyoxyethylene (20) sorbitan monooleate and from polyethylene glycol 4000/6000 did not differ from oral values (Kahela et al. 1987). On the other hand, rectal absorption was slower, with a t max of 1.1 to 1.6h, versus 0.6h after oral solution. Absorption from the fatty base was faster than from the hydrous base, possibly owing to the presence of a surfactant. Storage of the suppositories for 4 years at room temperature resulted in a decrease of absorption from those with a fatty base, which it was suggested was brought about by an increase in the crystalline stage of the base (Kahela et al. 1987). Walter-Sack et al. (1989) reported similar bioavailability after oral administration of SQlid and liquid formulations and after rectal delivery of paracetamol suppositories of unspecified composition. Also in the latter study, rectal absorption rate proved to be delayed compared with oral administration; consequently, the authors preferred oral administration in situations of medical urgency. From urinary excretion data in male volunteers, the rate and extent of paraceta mol absorption from 'Witepsol' H 15 and H 12 suppositories with added polyoxyethylene sorbitan monostearate ('Tween' 61) or polyoxyethylene monostearate ('Mirj' 53) appeared to be slightly higher than from 'Witepsol' HI5 or polyethylene glycol base alone (Abd Elbary et al. 1983). The bioavailability from suppositories with surfactants ranged between 103 and 109% relative to oral tablets, whereas 'Witepsol' HI5 and polyethylene glycol base resulted in values of 89 and 96%, respectively. Absorption data correlated with in vitro release, suggesting that surfactants increase absorption by increasing drug release. On the other hand, an enhancing action on mucosal permeability, possibly resulting in mucosal damage, may also contribute to the effect of surfactants (Van Hoogdalem et al. 1989a). Djimbo and Moes (1986) further investigated the influence of surfactants on paracetamol release from a fatty base. Various polyoxyethylene esters
111
and ethers proved to solubilise paracetamol, their effect increasing with chain length. Based on urinary excretion data in volunteers, 2% w/w of polyoxyethylene (20) sorbitan monooleate ('Tween' 80) enhanced rectal paracetamol bioavailability compared with fatty base alone. However, with a higher concentration of surfactant (5% w/w) this effect was lost, indicating the existence of an optimum between increasing drug release and decreasing the driving force for absorption. In contrast to the results presented above, Eandi et al. (1984) observed a low bioavailability for rectal paracetamol compared with oral values. Plasma data obtained in healthy adults indicated an absolute bioavailability of oral paracetamol tablets of 60 to 70%, whereas rectal delivery in unspecified suppositories resulted in values of 30 to 40% (Eandi et al. 1984). Absorption was relatively slow, since a Cmax of about 5 mgjL was reached within 2 to 3h after administration ofa Ig suppository. Incomplete rectal uptake, e.g. by poor drug release from the base, may be the underlying cause of this relatively low bioavailability; more extensive first-pass metabolism, as suggested by the authors, is unlikely to explain low rectal bioavailability, considering the higher oral values. Muller et al. (1984) reported a retardation of rectal paracetamol absorption after particle size reduction to ~1O~m, since on delivery in 'Witepsol' H15 t max was increased from 1.3 to 1.9h. It was suggested that decreasing particle size retarded the release from the molten base; however, the influence of coadministered surfactant 'Emulmetik' lbO, possibly lowering release by drug solubilisation, was not discussed. The pharmacokinetics of various rectal dosage forms of paracetamol were tested by analysis of saliva concentrations (Hagenlocher et al. 1987): the results demonstrated comparable bioavailability of paracetamol (~IO/oLm) in methylcellulose suspension, in hard gelatin capsules with amphiphilic (polyoxyethylene esters) or lipophilic (triglycerides) excipient, or in fatty suppositories, with values between 78 and 88% relative to oral delivery. The absorption rate, however, proved to be formulation-dependent, and decreased in the order mi-
112
Clin. Pharmacokinet. 21 (2) 1991
The potential for paracetamol to irritate the bowel was discussed in section 2.6.
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Fig. 7. (a) In vitro release and (b) mean saliva concentration versus time curves in volunteers obtained from different rectal formulations containing paracetamol 500mg (_ = lipophilic capsule; 0 = amphiphilic capsule; 0 = fatty suppository; • = microenema) and from an oral solution (.) [after Hagenlocher et at. 1987).
croenema > amphiphilic rectal capsule > lipophilic rectal capsule and suppository, not correlating with in vitro dissolution (fig. 7) [Hagenlocher et al. 1987]. Slower absorption from the lipophilic capsule and suppository may be related to a relatively high solubility in the base, retarding drug release in vivo (Kahela et al. 1987).
3.5.2 Indomethacin In a crossover study in healthy volunteers, a rectal solution of indomethacin sodium 100mg resulted in highly variable absolute bioavailabilities ranging between 37 and 112% (Moller Jensen & Grenabo 1985). The absorption rate was high, with t max varying between 10 and 30 min. On the other hand, administration in a suppository of unspecified base resulted in slower absorption with similarly variable bioavailability. In the light of its rapid absorption profile, the authors considered the rectal solution useful in the treatment of colic pain, although the observed variability is an important drawback (Moller Jensen & Grenabo 1985). The suppository base proved to have an important influence on the absorption profile of indomethacin. Compared with oral capsules, rectal indomethacin in polyethylene glycol base demonstrated incomplete absorption, relative mean bioavailability being 61 % in healthy subjects (Fredj et al. 1983). On the other hand, the absorption rate did not differ significantly with either route. In an extensive study, Moller (1984) compared the bioavailabilities of various rectal indomethacin l00mg formulations. Polyethylene glycol base displayed faster absorption than the lipophilic bases; t max was 1.9h and the extent of absorption was similar to the value reached with a rectal suspension in 1% methylcellulose, used as reference. Using the lipophilic 'Witepsol' bases W35, H 15 and H32, complete relative bioavailability was observed only for the first, the extent of absorption appearing to drop to 75% with the decreasing hydroxyl number of the lipophilic bases. The extent of absorption from rectal soft gelatin capsules with various fatty constituents was also lower than with the rectal suspension (Moller 1984). Jonkman et al. (1984) demonstrated bioequivalence in terms of both rate and extent of rectal indomethacin absorption after administration in polyethylene glycol base and in waxy base ('Suppocire' AP). After a dose of indomethacin 50mg, Cmax and t max values were 0.9 to 2.4 mg/L and 40
Pharmacokinetics of Drugs Administered Rectally
to 100 min, respectively, indicating considerable intraindividual variability. Local irritation was reported in I patient after administration of the polyethylene glycol suppository (Jonkman et al. 1984). 3.5.3 Dic/o/enac In healthy volunteers, diclofenac sodium 50mg in carboxypolymethylene gel resulted in a 28% higher rectal bioavailability compared with administration in fatty suppository base ('Voltaren' suppositories) [Morimoto et al. 1985]. In comparison with the suppositories, the gel base displayed a higher absorption rate: t max decreased from I to 0.25h and Cmax increased from 0.6 to l.0 mgjL, indicating impaired drug release from fatty suppositories. In rats, the gel preparation was reported to be less irritating to the rectal mucosa (Morimoto et al. 1985). Nishihata et al. (l986b) investigated the possibilities of preparing long-acting diclofenac suppositories with sustained drug release properties. Adding natural or hydrogenated soya lecithin delayed the in vitro dissolution rate of diclofenac sodium from glyceride suppositories. This property was confirmed in healthy volunteers, with lecithin increasing absorption t'l2 from 0.9 to at most 6.3h (Nishihata et al. 1986b). The extent of absorption was not affected, provided that sustained delivery was not interrupted by defaecation. The effectiveness of diclofenac suppositories in acute situations was recently demonstrated by Thompson et al. (1989). In that study, a single dose of rectal diclofenac 100mg proved to be an effective analgesic in renal colic. 3.5.4 Naproxen In healthy volunteers, the absolute bioavailability of fatty suppositories containing naproxen 125 to 500mg was estimated at 80%; mean t max varied between 1.4 and 2.4h (Calvo et al. 1987). A dose of 750mg resulted in relatively low plasma concentrations, and a bioavailability of 60% was calculated. It was suggested that this nonlinearity was caused by a decrease in plasma protein binding. However, another explanation, which was not considered by the authors, might be incomplete rectal
113
absorption from the high dose suppository. A somewhat slower absorption, resulting in a mean t max and Cmax of 3. lh and 55 mgjL, respectively, was reported by Guelen et al. (1988), who administered naproxen 500mg suppositories in an unspecified base to healthy volunteers. The use of suppositories containing 600mg of the piperazine salt of naproxen exhibited a relatively poor absorption profile in healthy volunteers (Maggi & Renzetti 1988). Bioavailability was 63% relative to oral tablets, and the mean t max was long at 3.8h. 3.5.5 Ibupro/en Ibuprofen solution (40 gjL; volume 20ml), rectally administered to healthy volunteers, showed non instantaneous absorption: mean t max was l.lh, compared with 0.33h after oral intake of the solution (Eller et al. 1989). The rectal bioavailability of the solution was 88% relative to the oral route, and comparable values were reported for suppositories (Becker et al. 1983). Application of a suspension of aluminium ibuprofen (80 mgjml; volume 10ml) resulted in poor absorption characteristics, with a relative bioavailability of 52% (Eller et al. 1989). 3.5.6 Ketopro/en Ketoprofen appears to be absorbed well from the human rectum, with a bioavailability approaching oral values (Becker et al. 1983). In healthy volunteers, ketoprofen 75mg in fatty suppositories was rapidly absorbed, mean t max and Cmax values being I.Dh and 5.7 mgjL, respectively (Kanamoto et al. 1988). Similar results were obtained with rectal delivery in gelatin encapsulated suppositories, and both formulations showed a decreased absorption rate in patients undergoing haemorrhoidectomy (Kanamoto et al. 1988). 3.5.7 Miscellaneous Flurbiprofen 50 or 75mg proved to be rapidly absorbed rectally in children aged 6 to 12 years, with t max varying between 0.5 and l.5h (Scaroni et al. 1984). Compared with oral administration as
Clin. Pharmacokinet. 21 (2) 1991
114
syrup, the rectal bioavailability appeared to be complete. In 3 male subjects, phenylbutazone 250mg was variably absorbed from a triglyceride suppository base, t max varying between 2 and 6h (John et al. 1983). Its bioavailability was estimated to be 77% relative to an oral suspension. Isoxicam 200 to 400mg in suppositories of unspecified nature proved to be slowly absorbed in healthy volunteers, mean t max being 13 to 15h (Accardo et al. 1983). The absorption and elimination kinetics of rectal isoxicam were comparable with those from oral administration, but mean bioavailability was 68 to 74% relative to oral capsules. In an interesting series of experiments, Moolenaar et al. (1984b) investigated the rectal absorption profile of diflunisal in humans, using various dosage forms. Absorption from a suspension in methylcellulose (pH 4.5) was incomplete, with a mean bioavailability amounting to 55% relative to oral suspension. However, improving drug solubility by neutralising the suspension increased this value to 74% and enhanced the rate of absorption (t max 2.2h; fig. 8). Another approach to increase solubility was the use of the solvents polyethylene glycol and glycofurol; the latter gave a plasma concentration profile comparable with the neutral suspension, with a relative bioavailability of 84%. It was emphasised that the use of solvents may reduce drug absorption by lowering thermodynamic activity (Moolenaar et al. I 984b). Use of suppositories of diflunisal sodium in 'Witepsol' HI5 or polyethylene glycols did not result in better absorption profiles than the solutions mentioned above. Interestingly, an increase in suppository volume raised the absorption rate, probably by increasing the surface area available for absorption (Moolenaar et al. I 984b). 3.6 Antibacterial Agents 3.6.1 Metronidazole Metronidazole is used extensively in the prophylaxis and treatment of anaerobic infections. For practical and economical reasons, attempts have been made to develop rectal metronidazole form-
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Fig. 8. Mean ± SD plasma concentration versus time curves of diflunisal after oral administration of a diflunisal 250mg suspension in water (0) and after rectal administration of diflunisal 250mg suspended in methylcellulose solution, pH 4.5 (0) and pH 7.0 (.), in 7 volunteers (after Moolenaar et at. 1984b).
ulations as alternatives for intravenous administration. As noted previously (Ralph 1983), the bioavailability of oral metronidazole approaches 100%, whereas rectal administration results in a figure of 70 to 80%. Time to Cmax was about 4h after administration of a suppository, whereas it was about I h with administration as an enema, resembling the oral absorption rate. It was considered that single-dose suppository administration might be inadequate for prophylaxis, because of slow drug absorption and, consequently, low plasma concentrations (Ralph 1983). Relatively fast rectal absorption of metronidazole from liquid formulations was confirmed by Yromans et al. (1984). In that study, an aqueous suspension of metronidazole 500mg (~45JLm) in methylcellulose 0.5% was administered to healthy volunteers, and mean t max and Cmax values of 1.3h and 4.8 mgfL, respectively, were reported. How-
Pharmacokinetics of Drugs Administered Rectally
ever, rectal drug uptake was incomplete, resulting in bioavailability ranging from 29 to 81 %, relative to an oral solution. Comparable values were observed with suppositories in a triglyceride base, although absorption from the latter formulation occurred more slowly (t max of 4h) [Vromans et al. 1984]. The low bioavailability from the fatty base was confirmed by Diquet et al. (1984), who administered metronidazole SOOmg in a glyceride base to patients who had undergone gastrointestinal surgery. Enhancement of the drug dissolution profile by using polyethylene glycol bases resulted in higher relative bioavailabilities, with mean values of 69 to 78%, and a Cmax of 6.8 myL was reached within 3h. These results demonstrate a slow but sustained absorption of metronidazole from solid suppository bases. The polyethylene glycol suppositories were considered to represent an adequate alternative to parenteral delivery, and also to be applicable in areas with a high environmental temperature (Vromans et al. 1984). In the light of the slow rectal absorption rate, Barker et al. (1983) used a combination of 2 metronidazole SOOmg intravenous infusions and 8-hourly delivery of Ig suppositories in patients with lifethreatening sepsis; the suppository base was not specified. In that procedure, rectal metronidazole found to be both practical and adequate, resulting in serum concentrations well above the minimum inhibitory concentration of 6.2 myL. In a related experimental procedure, Meijer et al. (1984) investigated the pharmacokinetics of 8hourly rectal metronidazole SOOmg, administered after multiple intravenous infusions had been given to reach steady-state. In this study, which was performed in patients who had undergone gynaecological surgery, rectal metronidazole was delivered as a suppository in 'Witepsol' HIS. Mean trough serum concentration (Cmin) and Cmax were 8.9 and 13 myL, respectively, which was felt to indicate effective prophylaxis of anaerobic infections. The absolute rectal bioavailability was estimated at 76% (Meijer et al. 1984). Similar data were reported by Harnoss et al. (198S) and Farinotti et al. (1984), who applied suppositories of metronidazole of Ig in a base of unspecified composition. In the latter
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study, additional intravenous therapy was considered necessary only in the case of emergency surgery, when preoperative rectal therapy is not possible. According to De Boer and Thornton (1989), 2 metronidazole Ig suppositories, administered before and after surgery, respectively, significantly reduced wound infections and febrile episodes in patients undergoing caesarian section. 3.6.2 Erythromycin In male volunteers, Pozzi et al. (1982) compared the absorption pharmacokinetics of erythromycin 2S0mg from fatty suppositories with those of oral erythromycin in enteric coated tablets, using a noncrossover study design. However, the restricted sampling procedure in that study did not allow a reliable determination of rate and extent of absorption. Oral and rectal bioavailability appeared to be similar, but rectal absorption was faster (tmax = Ih; Cmax = 0.8 myL), which was not surprising considering that coated tablets were used for oral administration. Absolute bioavailabilities were not determined; however, in the light of the relatively low absolute oral bioavailability from enteric coated capsules, viz. 38% (Mather et al. 1981), rectal absorption may be expected to be far from complete. Consequently, optimisation of the formulation seems to be indicated, although the suppositories used currently were reported to give therapeutic drug concentrations for several hours (Acerbi et al. 1983; Pozzi et al. 1982). 3.6.3 Ampicillin The poor rectal absorption of ampicillin has elicited attempts to develop rectal drug formulations with enhanced absorption. Murakami et al. (1983) investigated the effect of coadministration of dicloxacillin sodium 62.Smg and other isoxazolyl penicillins on the rectal absorption of ampicillin sodium 70 to 12Smg in healthy volunteers, using suppositories of 'Witepsol' H IS base. Isoxazolyl penicillins proved to enhance the urinary recovery of rectally administered ampicillin from I to 3% to, for example, 11 to 17% for dicloxacillin (fig. 9). The enhancing effect was possibly based
Clin. Pharmacokinet. 21 (2) 1991
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solved in 0.5% of methyl cellulose to healthy volunteers resulted in a mean ampicillin bioavailability of 30% relative to an oral suspension, indicating incomplete rectal absorption of bacampiciIIin. On the other hand, the oral and rectal absorption rates were comparably high, median t max being 0.75 and 0.5h, respectively. Mucosal irritation and diarrhoea were observed in 7 of 12 subjects (Sjovall et ai. 1984).
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Fig. 9. Urinary excretion of ampicillin sodium (0) and sodium salts of several isoxazolyl penicillins (II) after rectal
administration of ampicillin sodium 70mg with or without isoxazolyl penicillin sodium salt 140mg in 'Witepsol' HIS, as observed in I male volunteer; results are expressed in percentage of the dose excreted in 6h (after Murakami et al. 1983).
on the formation of penicillin-calcium complexes, resulting in improved mucosal permeability (Murakami et ai. 1983). However, the authors did not consider the possibility of an interaction with the elimination pharmacokinetics of ampicillin, resulting in increased urinary excretion. Furthermore, rectal irritation was reported for this formulation. Bergstrom et ai. (1988) investigated the clinical efficacy of suppositories containing sodium ampicillin 125 and 250mg, together with sodium decanoate 15 and 25mg as an absorption promoter. These suppositories were found to be effective in the treatment of otitis media in children, with plasma concentrations above 4 mg/L, 30 min after administration. However, the study was not placebo-controlled, thus hampering a clear evaluation of the efficacy of drug therapy. In addition, the suppositories caused irritation and gastrointestinal disturbances; hence, the value of this preparation in clinical therapy remains uncertain. Sjovall et ai. (1984) investigated the prodrug approach to enhancing rectal ampicillin absorption. Administration of bacampicillin HCl 400mg dis-
3.6.4 Miscellaneous Antibacterial Drugs Clofoctol, an antibacterial phenol derivative, was administered rectally to patients undergoing pulmonary resection (Del Tacca et ai. 1987). Two suppositories of clofoctol 750mg in an unspecified base demonstrated fast absorption with t max and C max values of 30 min and 38 mg/L, respectively, and high amounts (93 /lg/g) were reached in pulmonary tissue. Chiandussi et ai. (1988) investigated the rectal bioavailability of a combination of tetroxoprim 200mg and sulfadiazine 500mg in a triglyceride base. Compared with oral administration, rectal administration of both compounds was incomplete and very slow; using a restricted sampling protocol, mean t max values of7.5 and 8h were estimated for tetroxoprim and sulfadiazine, respectively. Urinary data indicated bioavailabilities of 58 and 24%, respectively. Although these results demonstrated an unsatisfactory rectal absorption profile, the therapeutic efficacy in respiratory and urinary infections was considered adequate (Chiandussi et ai. 1988).
3.7 Xanthine Drugs 3.7.1 Theophylline As reviewed previously, theophylline absorption from rectal solution is similar to oral absorption and generally occurs rapidly and completely (De Boer et ai. 1982). On the other hand, rectal absorption from suppositories may be variable and incomplete, microcrystalline theophylline in polyethylene glycol giving the best absorption profile (Tjandramaga et ai. 1979). With a suppository base consisting of 'Witepsol' H 15 and E75, aminophyl-
117
Pharmacokinetics of Drugs Administered Rectally
line tended to show faster and more extensive absorption than theophylline, with mean t max values of 2.8 and 3. lh, respectively, which may be explained by better aqueous solubility of aminophylline (Fujii et al. 1982). Aminophylline in 'Witepsol' and in polyethylene glycol-water suppositories showed comparable results (Fujii et al. 1982). Lyon and Mcintosh (l98S) successfully treated apnoea in preterm infants with aminophylline lO mg/kg/day in suppositories with an unspecified base. A rectal loading dose of 10 mg/kg proved necessary to establish the therapeutic effect within 24h; the mean steady-state concentration (CSS) was 12 mg/L. In male volunteers, theophylline absorption from an enema containing theophylline monoethanolamine was comparable with absorption from an oral elixir of unspecified composition, with a mean t max of 2.2 and 1.2h, respectively (Cole & Kunka 1984). The enema was therefore considered to be a suitable alternative to oral administration. In contrast, absorption from suppositories containing aminophylline in a base of oils and waxes was considerably slower [mean (±SD) t max = S.3 ± 3.4h], whereas the extent of absorption did not differ significantly (Cole & Kunka 1984). De Leede et al. (1982) compared the absorption profile of choline theophyllinate from a rectal osmotic delivery device with the profiles of an oral solution and of a suppository in 'Witepsol' HIS. Using the osmotic delivery system, in vitro and in vivo release were in good agreement, and the curves resembled those of a zero-order intravenous infusion. As might be expected from previous data oral absorption was rapid, t max being about 30 min, whereas the suppository demonstrated a rather slow uptake (tmax 2.Sh). The authors considered the osmotic delivery device to be a useful nonparenteral delivery system in clinical pharmacological studies in which steady-state drug concentrations are required (De Leede et al. 1982). Choline theophyllinate in hydrogels of hydroxyethyl methacrylate and ethylene glycol dimethacrylate as crosslinker also resulted in good agreement between in vitro and in vivo release profiles in male volunteers (De Leede et al. 1986). These formulations delivered
288mg of theophylline according to a matrix-type release pattern, resulting in near-constant plasma concentrations of about 2 mg/L. Hydrogels were suggested as promising rectal drug delivery systems with a predictable release profile, suitable for the administration of various drugs. Choline theophyllinate in aqueous solution was rectally administered to infants (age 14 to 44 months) with acute asthma (Kuzemko et al. 1985). Rectal doses of S.4 to 7.4 mg/kg resulted in plasma concentrations of 4. 7 to 11.2 mg/L and good clinical efficacy. This formulation was recommended as a suitable alternative to oral or inhalant medication. In an interesting report, Hooker et al. (1989) described the absorption profile of theophylline from colostomies in human subjects. After administration of a solution of aminophylline 300mg via the colon stoma, mean Cmax and t max were 6.2 mg/L and I.7h, respectively, indicating relatively rapid absorption. The extent of absorption was quite variable (between 19 and 123%), and the mean bioavailability amounted to 61 % relative to the oral solution. Three of 9 patients were unable to retain the solution administered via the colostomy, possibly because of local irritation, which is likely to contribute to the incomplete and variable colonic absorption. 3.7.2 Enprofylline The absorption of enprofylline, a bronchodilating xanthine drug which is poorly metabolised, was investigated in male volunteers after oral, intraduodenal and rectal delivery (Lunell et al. 1984). Rectal administration from an aqueous solution was somewhat slow compared with oral and duodenal uptake, with a t max of2.6h, O.Sh and 13 min, respectively. Oral absorption was complete, whereas urinary data indicated an absolute rectal bioavailability of about 89%.
3.8 Anticancer Agents 3.B.1 Tamoxifen The occurrence of nausea and vomiting in patients undergoing cancer chemotherapy with tamoxifen has stimulated research towards the de-
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velopment of a rectal formulation of that compound. Tukker et al. (1986) investigated the bioavailability of tamoxifen 40mg in 'Witepsol' H 15 and 'Suppocire AML' in healthy male volunteers. The drug was poorly and slowly absorbed from 'Witepsol' H 15 suppositories, resulting in a bioavailability of 20 to 40% relative to oral tablets. The 'Suppocire AML' displayed a worse performance, which may be related to the presence of lecithin, lowering the driving force for tamoxifen absorption. The low bioavailability from suppositories may be based on the lipophilicity of the drug, resulting in the observed poor in vitro release and in poor solubility in the rectal fluid (Tukker et al. 1986). No attempts were made to optimise the formulation by using a polyethylene glycol base, thus possibly enhancing in vitro drug release. The results should be interpreted in light of the fact that the suppositories were prepared from ground tablets, and the possible influence of tablet constituents on drug absorption was unclear.
3.B.2 Fluorouracil In a relatively small study, Takahashi et al. (1988) investigated the etTect of irradiation combined with rectal fluorouracil on the local recurrence of rectal carcinoma in cancer patients. Preoperative irradiation combined with 20 days' treatment with fluorouracil 100mg suppositories seemed to reduce lymph node metastases; however, further studies are necessary before the value of this approach to cancer therapy can be fully evaluated. 3.B.3 Medroxyprogesterone Acetate Medroxyprogesterone acetate is a progestational agent used in the treatment of metastatic breast cancer. As the oral availability of the drug is poor and erratic, Pannuti et al. (1986) investigated the applicability of medroxyprogesterone acetate 500mg in cocoa bu,tter suppositories. Rectal absorption was both slow and low, t max and Cmax being 4 to 8h and 0.8 to 3.3 J.tg/L, respectively, whereas the same dose administered orally showed values of 2h and 9.9 J.tg/L, respectively. It is conceivable that rectal absorption may be enhanced by employing a poly-
C/in. Pharmacokinet. 21 (2) 1991
ethylene glycol base, because the cocoa butter base may cause inetTective release of this lipophilic compound. 3.9 Drugs in Inflammatory Bowel Disease
3.9.1 Mesalazine and Derivatives Mesalazine is the active moiety of sulfasalazine, used in the treatment of inflammatory bowel disease. It is liberated from the orally administered parent drug in the colon by bacterial splitting of the azo bond (Brogden & Sorkin 1989; Jarnerot 1989). Since oral mesalazine is etTectively absorbed from the small intestine, the sulfapyridine part of sulfasalazine can be considered to be the carrier of mesalazine to the inflamed colon. As the adverse etTects of oral sulfasalazine are ascribed to the sulfapyridine moiety, etTorts have been undertaken to develop alternative colon-specific formulations of mesalazine without sulfapyridine, and with low systemic bioavailability, as reviewed by Jarnerot (1989) and by Brogden & Sorkin (1989). The use of enemas is a frequent approach (Hanauer 1989), and recently Sutherland et al. (1987) reported the etTectiveness of 60ml suspension enemas of mesalazine 4g as assessed in patients with ulcerative colitis of the distal colon. A suspension of mesalazine 4g in 100mi of vehicle, rectally administered to patients with ulcerative colitis, resulted in slow absorption, the Cmax of total drug being reached in 3 to 6h (Cam pieri et al. 1985). The drug was primarily present in plasma in its acetylated form and peak levels did not exceed 7 mg/L. Raising the enema volume to 200ml resulted in an increase in the amount absorbed, probably through an increase in the surface area available for absorption. Urinary data indicated incomplete colonic absorption of mesalazine, the fraction of the dose renally excreted in 24h not exceeding 37% (Cam pieri et al. 1985; Sutherland et al. 1987). With a suspension enema containing mesalazine 700mg similar results were obtained in patients with colitis and proctitis (Dew et al. 1983). Bondesen et al. (1988) compared the absorption characteristics of mesalazine 500mg in neutral phosphate butTer, instilled in the colon and rectum
Pharmacokinetics of Drugs Administered Rectally
of patients undergoing colonoscopy. Absorption appeared to be incomplete and variable; total amounts of drug excreted renally after colonic and rectal instillation were 20 to 4S% and II to 87%, respectively, of the administered dose. Another approach was followed by Allgayer et al. (1984), who investigated the absorption of solfasalazine from a 3g enema in patients with ulcerative colitis. Rectal absorption of the conjugate appeared to be faster, compared with the results cited above for unconjugated mesalazine, with a t max of 3h. On the other hand, concentrations of sulfasalazine and liberated sulfapyridine were lower after rectal administration than with oral tablets, which was considered a probable explanation for the low frequency of adverse effects from the rectal route (Allgayer et al. 1984). Sandberg-Gertzen et al. (1983) evaluated the rectal absorption profile of azodisal sodium, an azo bond-containing compound which may be split by colonic microorganisms into 2 mesalazine molecules. In healthy volunteers, an enema of azodisal sodium 2g in 100ml resulted in a mean Cmax of 2.1 mg/L of parent compound, reached in O.S to 2h, indicating relatively fast uptake. However, absorption was incomplete compared with the oral data, and I to 17% of the dose was excreted renally as parent drug and metabolites in 24h (SandbergGertzen et al. 1983). 3.9.2 Corticosteroids Rectal instillation of corticosteroids is now a well established approach in the treatment of inflammatory bowel disease. Since only a topical effect is intended, corticosteroids which show high efficacy and low systemic drug concentrations are preferred, in order to minimise adrenal suppression and other adverse effects inherent to steroid therapy. Therefore, corticosteroids and drug formulations displaying poor absorption or high firstpass metabolism are advisable. As outlined by Mulder et al. (1989), rectal prednisolone metasulfobenzoate, budesonide, tixocortol pivalate and beclomethasone diproprionate appear to interfere less with adrenocortical function, compared with hy-
119
drocortisone acetate, prednisolone-21-phosphate and betamethasone. In clinical practice, steroid enemas prove to be difficult to retain, because of their large volume. Foam preparations appear to be better accepted, as described recently for a Sml hydrocortisone acetate foam (Neumann et al. 1989). In the latter trial, which was noncomparative, the foam was reported to be clinically effective, and systemic absorption was considered to be insignificant, judging from the lack of effect on serum cortisol levels. However, interpretation of these data is hazardous, because the procedure did not discriminate between exogenous (hydrocortisone) and endogenous cortisol. Cann and Holdsworth (1987) also investigated the systemic absorption of hydrocortisone acetate foam in patients with colitis, the endogenous production of cortisol being suppressed by dexamethasone. In that study, the foam, which contained a dose of hydrocortisone acetate 12Smg, resulted in a considerable rise in plasma cortisol levels, peak values of 82 to 370 ~gjL being reached in 4h. On the other hand, oral absorption of hydrocortisone acetate 20mg was faster, resulting in a t max ofO.Sh (Cann & Holdsworth 1987). The authors acknowledged the possibility of adrenal suppression and other adverse effects after application of the foam. Application of 20ml of a foam containing prednisolone metasulfobenzoate 20mg in patients with ulcerative colitis resulted in prednisolone concentrations in plasma and mucosal tissue comparable with those after an enema of prednisolone metasulfobenzoate 60mg in looml of vehicle (Rodrigues et al. 1987). It was suggested that the high concentration in foam resulted in more effective colonic absorption. A transient adrenal suppression was observed. Enemas containing prednisolone metasulfobenzoate proved to result in lower plasma prednisolone concentrations than obtained with prednisolone-21-phosphate (Lee et al. 1980; Rodrigues et al. 1987). 3.10 Cardiovascular Active Drugs 3.10.1 Nifedipine Rate-controlled rectal drug delivery of nifedipine I.S mgjh by an osmotic delivery device in healthy volunteers resulted in steady-state plasma
120
concentrations of 14 to 27 jJ.g/L (Kleinbloesem et al. 1984). Interestingly, the low input rate resulted in a bl00d pressure-lowering effect without concurrent reflex tachycardia. In the latter study, the use of sodium salicylate 10 mg/ml and ethanol (1 mg/ml) was necessary to prepare an aqueous formulation of the lipophilic drug nifedipine 22 mg/ml. Use of a polyethylene glycol base is indicated when developing a preparation of nifedipine in the light of the above mentioned lipophilic character of this drug. Hence, Kurosawa et al. (1985) tested the absorption behaviour of nifedipine 10mg in healthy males, using a suppository base consisting of polyethylene glycols 400 and 4000. Rectal absorption was appreciable, resulting in a mean t max and Cmax of 1.75h and 68 jJ.g/L, respectively, whereas values of 0.78h and 110 jJ.g/L were found with oral soft gelatin capsules. The extent of absorption was comparable with both routes. In contrast to oral capsules, suppository administration significantly reduced systolic and diastolic blood pressure, without affecting the heart rate (fig. 10) [Kurosawa et al. 1985], confirming the results of Kleinbloesem et al. (1984). This pharmacokinetic and pharmacodynamic profile of rectal nifedipine was further confirmed in a later study by Kurosawa et al. (1987), which was performed in hypertension patients. The suppository was found to be useful in the management of hypertensive emergencies; application as a rectal sustained release formulation in long term hypertension treatment, as suggested by the authors, may be less practical. 3.10.2 Flecainide Acetate Lie-A-Huen and Kingma (1988) investigated the rectal absorption behaviour of flecainide acetate in a patient who responded poorly to oral flecainide, possibly because of a previous subtotal gastric resection. Flecainide acetate 200mg administered as a microenema showed rapid absorption (t max 1.5h) and complete absolute bioavailability. In addition, the absorption from a polyethylene glycol base was acceptable, t max and absolute bioavailability being 3.5h and 80%, respectively. Subsequent treatment with this suppository adequately controlled tachycardias in the patient. In contrast, absorption from
Clin. Pharmacokinet. 21 (2) 1991
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Pharmacokinetics of Rectal Drug Administration, Part II Clinical Applications of Peripherally Acting Drugs, and Conclusions Ewoud J. van Hoogdalem . Albertus G, de Boer and Douwe D, Breimer Brocades Pharma B.Y., Delft, and Center for Biopharmaceutical Sciences, Division of Pharmacology, Sylvius Laboratories, University of Leiden, Leiden, The Netherlands
Contents 110 110 114 1/6 II" 118 119 /10 112 123
Summary
Summary 3.5 Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs 3.6 Antibacterial Agents 3.7 Xanthine Drugs 3.8 Anticancer Agents 3.9 Drugs in Inflammatory Bowel Disease 3. 10 Cardiovascular Active Drugs 3.11 Miscellaneous 4. Enhancement of Rectal Drug Absorption 5. Conclusions
Part I of this article, which appeared in the previous issue of the Journal, covered general considerations, the physiology of the rectum, spreading of drugs into the colon, rectal absorption, partial avoidance of first-pass elimination, rate-controlled rectal delivery of drugs, irritation of the rectal mucosa and clinical applications of rectal administration, and discussed centrally acting drugs. In Part II, this discussion is extended to drugs which act peripherally and to methods of enhancing rectal drug absorption. The overall summary appeared in Part I.
3.5 Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs Rectal administration of non-narcotic analgesics may be indicated in various circumstances, e,g. in patients with nausea or vomiting or who are otherwise unable to take oral medication (infants), and also to avoid local irritation of the upper gastrointestinal tract. Therefore, the feasibility of rectal administration has been the topic of various studies with drugs of this class.
3.5.1 Paracetamol Rectally administered aqueous suspensions of paracetamol resulted in bioavailabilities which were comparable with those observed after oral administration, with the extent of absorption increasing with the volume of the suspension (Moolenaar et al. 1979). The rectal bioavailability of a 20ml suspension of paracetamol Ig was 91 %, relative to oral delivery, and similar results were obtained in children after rectal administration of paracetamol 20 mg/kg as an aqueous solution (Gaudreault et al.
Pharmacokinetics of Drugs Administered Rectally
1988). The latter treatment was not considered to be effective in preventing postoperative pain in children undergoing adenotonsillectomy. Concerning absorption from suppositories, the bioavailability from a fatty base with 0.8% of polyoxyethylene (20) sorbitan monooleate and from polyethylene glycol 4000/6000 did not differ from oral values (Kahela et al. 1987). On the other hand, rectal absorption was slower, with a t max of 1.1 to 1.6h, versus 0.6h after oral solution. Absorption from the fatty base was faster than from the hydrous base, possibly owing to the presence of a surfactant. Storage of the suppositories for 4 years at room temperature resulted in a decrease of absorption from those with a fatty base, which it was suggested was brought about by an increase in the crystalline stage of the base (Kahela et al. 1987). Walter-Sack et al. (1989) reported similar bioavailability after oral administration of SQlid and liquid formulations and after rectal delivery of paracetamol suppositories of unspecified composition. Also in the latter study, rectal absorption rate proved to be delayed compared with oral administration; consequently, the authors preferred oral administration in situations of medical urgency. From urinary excretion data in male volunteers, the rate and extent of paraceta mol absorption from 'Witepsol' H 15 and H 12 suppositories with added polyoxyethylene sorbitan monostearate ('Tween' 61) or polyoxyethylene monostearate ('Mirj' 53) appeared to be slightly higher than from 'Witepsol' HI5 or polyethylene glycol base alone (Abd Elbary et al. 1983). The bioavailability from suppositories with surfactants ranged between 103 and 109% relative to oral tablets, whereas 'Witepsol' HI5 and polyethylene glycol base resulted in values of 89 and 96%, respectively. Absorption data correlated with in vitro release, suggesting that surfactants increase absorption by increasing drug release. On the other hand, an enhancing action on mucosal permeability, possibly resulting in mucosal damage, may also contribute to the effect of surfactants (Van Hoogdalem et al. 1989a). Djimbo and Moes (1986) further investigated the influence of surfactants on paracetamol release from a fatty base. Various polyoxyethylene esters
111
and ethers proved to solubilise paracetamol, their effect increasing with chain length. Based on urinary excretion data in volunteers, 2% w/w of polyoxyethylene (20) sorbitan monooleate ('Tween' 80) enhanced rectal paracetamol bioavailability compared with fatty base alone. However, with a higher concentration of surfactant (5% w/w) this effect was lost, indicating the existence of an optimum between increasing drug release and decreasing the driving force for absorption. In contrast to the results presented above, Eandi et al. (1984) observed a low bioavailability for rectal paracetamol compared with oral values. Plasma data obtained in healthy adults indicated an absolute bioavailability of oral paracetamol tablets of 60 to 70%, whereas rectal delivery in unspecified suppositories resulted in values of 30 to 40% (Eandi et al. 1984). Absorption was relatively slow, since a Cmax of about 5 mgjL was reached within 2 to 3h after administration ofa Ig suppository. Incomplete rectal uptake, e.g. by poor drug release from the base, may be the underlying cause of this relatively low bioavailability; more extensive first-pass metabolism, as suggested by the authors, is unlikely to explain low rectal bioavailability, considering the higher oral values. Muller et al. (1984) reported a retardation of rectal paracetamol absorption after particle size reduction to ~1O~m, since on delivery in 'Witepsol' H15 t max was increased from 1.3 to 1.9h. It was suggested that decreasing particle size retarded the release from the molten base; however, the influence of coadministered surfactant 'Emulmetik' lbO, possibly lowering release by drug solubilisation, was not discussed. The pharmacokinetics of various rectal dosage forms of paracetamol were tested by analysis of saliva concentrations (Hagenlocher et al. 1987): the results demonstrated comparable bioavailability of paracetamol (~IO/oLm) in methylcellulose suspension, in hard gelatin capsules with amphiphilic (polyoxyethylene esters) or lipophilic (triglycerides) excipient, or in fatty suppositories, with values between 78 and 88% relative to oral delivery. The absorption rate, however, proved to be formulation-dependent, and decreased in the order mi-
112
Clin. Pharmacokinet. 21 (2) 1991
The potential for paracetamol to irritate the bowel was discussed in section 2.6.
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Fig. 7. (a) In vitro release and (b) mean saliva concentration versus time curves in volunteers obtained from different rectal formulations containing paracetamol 500mg (_ = lipophilic capsule; 0 = amphiphilic capsule; 0 = fatty suppository; • = microenema) and from an oral solution (.) [after Hagenlocher et at. 1987).
croenema > amphiphilic rectal capsule > lipophilic rectal capsule and suppository, not correlating with in vitro dissolution (fig. 7) [Hagenlocher et al. 1987]. Slower absorption from the lipophilic capsule and suppository may be related to a relatively high solubility in the base, retarding drug release in vivo (Kahela et al. 1987).
3.5.2 Indomethacin In a crossover study in healthy volunteers, a rectal solution of indomethacin sodium 100mg resulted in highly variable absolute bioavailabilities ranging between 37 and 112% (Moller Jensen & Grenabo 1985). The absorption rate was high, with t max varying between 10 and 30 min. On the other hand, administration in a suppository of unspecified base resulted in slower absorption with similarly variable bioavailability. In the light of its rapid absorption profile, the authors considered the rectal solution useful in the treatment of colic pain, although the observed variability is an important drawback (Moller Jensen & Grenabo 1985). The suppository base proved to have an important influence on the absorption profile of indomethacin. Compared with oral capsules, rectal indomethacin in polyethylene glycol base demonstrated incomplete absorption, relative mean bioavailability being 61 % in healthy subjects (Fredj et al. 1983). On the other hand, the absorption rate did not differ significantly with either route. In an extensive study, Moller (1984) compared the bioavailabilities of various rectal indomethacin l00mg formulations. Polyethylene glycol base displayed faster absorption than the lipophilic bases; t max was 1.9h and the extent of absorption was similar to the value reached with a rectal suspension in 1% methylcellulose, used as reference. Using the lipophilic 'Witepsol' bases W35, H 15 and H32, complete relative bioavailability was observed only for the first, the extent of absorption appearing to drop to 75% with the decreasing hydroxyl number of the lipophilic bases. The extent of absorption from rectal soft gelatin capsules with various fatty constituents was also lower than with the rectal suspension (Moller 1984). Jonkman et al. (1984) demonstrated bioequivalence in terms of both rate and extent of rectal indomethacin absorption after administration in polyethylene glycol base and in waxy base ('Suppocire' AP). After a dose of indomethacin 50mg, Cmax and t max values were 0.9 to 2.4 mg/L and 40
Pharmacokinetics of Drugs Administered Rectally
to 100 min, respectively, indicating considerable intraindividual variability. Local irritation was reported in I patient after administration of the polyethylene glycol suppository (Jonkman et al. 1984). 3.5.3 Dic/o/enac In healthy volunteers, diclofenac sodium 50mg in carboxypolymethylene gel resulted in a 28% higher rectal bioavailability compared with administration in fatty suppository base ('Voltaren' suppositories) [Morimoto et al. 1985]. In comparison with the suppositories, the gel base displayed a higher absorption rate: t max decreased from I to 0.25h and Cmax increased from 0.6 to l.0 mgjL, indicating impaired drug release from fatty suppositories. In rats, the gel preparation was reported to be less irritating to the rectal mucosa (Morimoto et al. 1985). Nishihata et al. (l986b) investigated the possibilities of preparing long-acting diclofenac suppositories with sustained drug release properties. Adding natural or hydrogenated soya lecithin delayed the in vitro dissolution rate of diclofenac sodium from glyceride suppositories. This property was confirmed in healthy volunteers, with lecithin increasing absorption t'l2 from 0.9 to at most 6.3h (Nishihata et al. 1986b). The extent of absorption was not affected, provided that sustained delivery was not interrupted by defaecation. The effectiveness of diclofenac suppositories in acute situations was recently demonstrated by Thompson et al. (1989). In that study, a single dose of rectal diclofenac 100mg proved to be an effective analgesic in renal colic. 3.5.4 Naproxen In healthy volunteers, the absolute bioavailability of fatty suppositories containing naproxen 125 to 500mg was estimated at 80%; mean t max varied between 1.4 and 2.4h (Calvo et al. 1987). A dose of 750mg resulted in relatively low plasma concentrations, and a bioavailability of 60% was calculated. It was suggested that this nonlinearity was caused by a decrease in plasma protein binding. However, another explanation, which was not considered by the authors, might be incomplete rectal
113
absorption from the high dose suppository. A somewhat slower absorption, resulting in a mean t max and Cmax of 3. lh and 55 mgjL, respectively, was reported by Guelen et al. (1988), who administered naproxen 500mg suppositories in an unspecified base to healthy volunteers. The use of suppositories containing 600mg of the piperazine salt of naproxen exhibited a relatively poor absorption profile in healthy volunteers (Maggi & Renzetti 1988). Bioavailability was 63% relative to oral tablets, and the mean t max was long at 3.8h. 3.5.5 Ibupro/en Ibuprofen solution (40 gjL; volume 20ml), rectally administered to healthy volunteers, showed non instantaneous absorption: mean t max was l.lh, compared with 0.33h after oral intake of the solution (Eller et al. 1989). The rectal bioavailability of the solution was 88% relative to the oral route, and comparable values were reported for suppositories (Becker et al. 1983). Application of a suspension of aluminium ibuprofen (80 mgjml; volume 10ml) resulted in poor absorption characteristics, with a relative bioavailability of 52% (Eller et al. 1989). 3.5.6 Ketopro/en Ketoprofen appears to be absorbed well from the human rectum, with a bioavailability approaching oral values (Becker et al. 1983). In healthy volunteers, ketoprofen 75mg in fatty suppositories was rapidly absorbed, mean t max and Cmax values being I.Dh and 5.7 mgjL, respectively (Kanamoto et al. 1988). Similar results were obtained with rectal delivery in gelatin encapsulated suppositories, and both formulations showed a decreased absorption rate in patients undergoing haemorrhoidectomy (Kanamoto et al. 1988). 3.5.7 Miscellaneous Flurbiprofen 50 or 75mg proved to be rapidly absorbed rectally in children aged 6 to 12 years, with t max varying between 0.5 and l.5h (Scaroni et al. 1984). Compared with oral administration as
Clin. Pharmacokinet. 21 (2) 1991
114
syrup, the rectal bioavailability appeared to be complete. In 3 male subjects, phenylbutazone 250mg was variably absorbed from a triglyceride suppository base, t max varying between 2 and 6h (John et al. 1983). Its bioavailability was estimated to be 77% relative to an oral suspension. Isoxicam 200 to 400mg in suppositories of unspecified nature proved to be slowly absorbed in healthy volunteers, mean t max being 13 to 15h (Accardo et al. 1983). The absorption and elimination kinetics of rectal isoxicam were comparable with those from oral administration, but mean bioavailability was 68 to 74% relative to oral capsules. In an interesting series of experiments, Moolenaar et al. (1984b) investigated the rectal absorption profile of diflunisal in humans, using various dosage forms. Absorption from a suspension in methylcellulose (pH 4.5) was incomplete, with a mean bioavailability amounting to 55% relative to oral suspension. However, improving drug solubility by neutralising the suspension increased this value to 74% and enhanced the rate of absorption (t max 2.2h; fig. 8). Another approach to increase solubility was the use of the solvents polyethylene glycol and glycofurol; the latter gave a plasma concentration profile comparable with the neutral suspension, with a relative bioavailability of 84%. It was emphasised that the use of solvents may reduce drug absorption by lowering thermodynamic activity (Moolenaar et al. I 984b). Use of suppositories of diflunisal sodium in 'Witepsol' HI5 or polyethylene glycols did not result in better absorption profiles than the solutions mentioned above. Interestingly, an increase in suppository volume raised the absorption rate, probably by increasing the surface area available for absorption (Moolenaar et al. I 984b). 3.6 Antibacterial Agents 3.6.1 Metronidazole Metronidazole is used extensively in the prophylaxis and treatment of anaerobic infections. For practical and economical reasons, attempts have been made to develop rectal metronidazole form-
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Fig. 8. Mean ± SD plasma concentration versus time curves of diflunisal after oral administration of a diflunisal 250mg suspension in water (0) and after rectal administration of diflunisal 250mg suspended in methylcellulose solution, pH 4.5 (0) and pH 7.0 (.), in 7 volunteers (after Moolenaar et at. 1984b).
ulations as alternatives for intravenous administration. As noted previously (Ralph 1983), the bioavailability of oral metronidazole approaches 100%, whereas rectal administration results in a figure of 70 to 80%. Time to Cmax was about 4h after administration of a suppository, whereas it was about I h with administration as an enema, resembling the oral absorption rate. It was considered that single-dose suppository administration might be inadequate for prophylaxis, because of slow drug absorption and, consequently, low plasma concentrations (Ralph 1983). Relatively fast rectal absorption of metronidazole from liquid formulations was confirmed by Yromans et al. (1984). In that study, an aqueous suspension of metronidazole 500mg (~45JLm) in methylcellulose 0.5% was administered to healthy volunteers, and mean t max and Cmax values of 1.3h and 4.8 mgfL, respectively, were reported. How-
Pharmacokinetics of Drugs Administered Rectally
ever, rectal drug uptake was incomplete, resulting in bioavailability ranging from 29 to 81 %, relative to an oral solution. Comparable values were observed with suppositories in a triglyceride base, although absorption from the latter formulation occurred more slowly (t max of 4h) [Vromans et al. 1984]. The low bioavailability from the fatty base was confirmed by Diquet et al. (1984), who administered metronidazole SOOmg in a glyceride base to patients who had undergone gastrointestinal surgery. Enhancement of the drug dissolution profile by using polyethylene glycol bases resulted in higher relative bioavailabilities, with mean values of 69 to 78%, and a Cmax of 6.8 myL was reached within 3h. These results demonstrate a slow but sustained absorption of metronidazole from solid suppository bases. The polyethylene glycol suppositories were considered to represent an adequate alternative to parenteral delivery, and also to be applicable in areas with a high environmental temperature (Vromans et al. 1984). In the light of the slow rectal absorption rate, Barker et al. (1983) used a combination of 2 metronidazole SOOmg intravenous infusions and 8-hourly delivery of Ig suppositories in patients with lifethreatening sepsis; the suppository base was not specified. In that procedure, rectal metronidazole found to be both practical and adequate, resulting in serum concentrations well above the minimum inhibitory concentration of 6.2 myL. In a related experimental procedure, Meijer et al. (1984) investigated the pharmacokinetics of 8hourly rectal metronidazole SOOmg, administered after multiple intravenous infusions had been given to reach steady-state. In this study, which was performed in patients who had undergone gynaecological surgery, rectal metronidazole was delivered as a suppository in 'Witepsol' HIS. Mean trough serum concentration (Cmin) and Cmax were 8.9 and 13 myL, respectively, which was felt to indicate effective prophylaxis of anaerobic infections. The absolute rectal bioavailability was estimated at 76% (Meijer et al. 1984). Similar data were reported by Harnoss et al. (198S) and Farinotti et al. (1984), who applied suppositories of metronidazole of Ig in a base of unspecified composition. In the latter
115
study, additional intravenous therapy was considered necessary only in the case of emergency surgery, when preoperative rectal therapy is not possible. According to De Boer and Thornton (1989), 2 metronidazole Ig suppositories, administered before and after surgery, respectively, significantly reduced wound infections and febrile episodes in patients undergoing caesarian section. 3.6.2 Erythromycin In male volunteers, Pozzi et al. (1982) compared the absorption pharmacokinetics of erythromycin 2S0mg from fatty suppositories with those of oral erythromycin in enteric coated tablets, using a noncrossover study design. However, the restricted sampling procedure in that study did not allow a reliable determination of rate and extent of absorption. Oral and rectal bioavailability appeared to be similar, but rectal absorption was faster (tmax = Ih; Cmax = 0.8 myL), which was not surprising considering that coated tablets were used for oral administration. Absolute bioavailabilities were not determined; however, in the light of the relatively low absolute oral bioavailability from enteric coated capsules, viz. 38% (Mather et al. 1981), rectal absorption may be expected to be far from complete. Consequently, optimisation of the formulation seems to be indicated, although the suppositories used currently were reported to give therapeutic drug concentrations for several hours (Acerbi et al. 1983; Pozzi et al. 1982). 3.6.3 Ampicillin The poor rectal absorption of ampicillin has elicited attempts to develop rectal drug formulations with enhanced absorption. Murakami et al. (1983) investigated the effect of coadministration of dicloxacillin sodium 62.Smg and other isoxazolyl penicillins on the rectal absorption of ampicillin sodium 70 to 12Smg in healthy volunteers, using suppositories of 'Witepsol' H IS base. Isoxazolyl penicillins proved to enhance the urinary recovery of rectally administered ampicillin from I to 3% to, for example, 11 to 17% for dicloxacillin (fig. 9). The enhancing effect was possibly based
Clin. Pharmacokinet. 21 (2) 1991
116
solved in 0.5% of methyl cellulose to healthy volunteers resulted in a mean ampicillin bioavailability of 30% relative to an oral suspension, indicating incomplete rectal absorption of bacampiciIIin. On the other hand, the oral and rectal absorption rates were comparably high, median t max being 0.75 and 0.5h, respectively. Mucosal irritation and diarrhoea were observed in 7 of 12 subjects (Sjovall et ai. 1984).
25
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Fig. 9. Urinary excretion of ampicillin sodium (0) and sodium salts of several isoxazolyl penicillins (II) after rectal
administration of ampicillin sodium 70mg with or without isoxazolyl penicillin sodium salt 140mg in 'Witepsol' HIS, as observed in I male volunteer; results are expressed in percentage of the dose excreted in 6h (after Murakami et al. 1983).
on the formation of penicillin-calcium complexes, resulting in improved mucosal permeability (Murakami et ai. 1983). However, the authors did not consider the possibility of an interaction with the elimination pharmacokinetics of ampicillin, resulting in increased urinary excretion. Furthermore, rectal irritation was reported for this formulation. Bergstrom et ai. (1988) investigated the clinical efficacy of suppositories containing sodium ampicillin 125 and 250mg, together with sodium decanoate 15 and 25mg as an absorption promoter. These suppositories were found to be effective in the treatment of otitis media in children, with plasma concentrations above 4 mg/L, 30 min after administration. However, the study was not placebo-controlled, thus hampering a clear evaluation of the efficacy of drug therapy. In addition, the suppositories caused irritation and gastrointestinal disturbances; hence, the value of this preparation in clinical therapy remains uncertain. Sjovall et ai. (1984) investigated the prodrug approach to enhancing rectal ampicillin absorption. Administration of bacampicillin HCl 400mg dis-
3.6.4 Miscellaneous Antibacterial Drugs Clofoctol, an antibacterial phenol derivative, was administered rectally to patients undergoing pulmonary resection (Del Tacca et ai. 1987). Two suppositories of clofoctol 750mg in an unspecified base demonstrated fast absorption with t max and C max values of 30 min and 38 mg/L, respectively, and high amounts (93 /lg/g) were reached in pulmonary tissue. Chiandussi et ai. (1988) investigated the rectal bioavailability of a combination of tetroxoprim 200mg and sulfadiazine 500mg in a triglyceride base. Compared with oral administration, rectal administration of both compounds was incomplete and very slow; using a restricted sampling protocol, mean t max values of7.5 and 8h were estimated for tetroxoprim and sulfadiazine, respectively. Urinary data indicated bioavailabilities of 58 and 24%, respectively. Although these results demonstrated an unsatisfactory rectal absorption profile, the therapeutic efficacy in respiratory and urinary infections was considered adequate (Chiandussi et ai. 1988).
3.7 Xanthine Drugs 3.7.1 Theophylline As reviewed previously, theophylline absorption from rectal solution is similar to oral absorption and generally occurs rapidly and completely (De Boer et ai. 1982). On the other hand, rectal absorption from suppositories may be variable and incomplete, microcrystalline theophylline in polyethylene glycol giving the best absorption profile (Tjandramaga et ai. 1979). With a suppository base consisting of 'Witepsol' H 15 and E75, aminophyl-
117
Pharmacokinetics of Drugs Administered Rectally
line tended to show faster and more extensive absorption than theophylline, with mean t max values of 2.8 and 3. lh, respectively, which may be explained by better aqueous solubility of aminophylline (Fujii et al. 1982). Aminophylline in 'Witepsol' and in polyethylene glycol-water suppositories showed comparable results (Fujii et al. 1982). Lyon and Mcintosh (l98S) successfully treated apnoea in preterm infants with aminophylline lO mg/kg/day in suppositories with an unspecified base. A rectal loading dose of 10 mg/kg proved necessary to establish the therapeutic effect within 24h; the mean steady-state concentration (CSS) was 12 mg/L. In male volunteers, theophylline absorption from an enema containing theophylline monoethanolamine was comparable with absorption from an oral elixir of unspecified composition, with a mean t max of 2.2 and 1.2h, respectively (Cole & Kunka 1984). The enema was therefore considered to be a suitable alternative to oral administration. In contrast, absorption from suppositories containing aminophylline in a base of oils and waxes was considerably slower [mean (±SD) t max = S.3 ± 3.4h], whereas the extent of absorption did not differ significantly (Cole & Kunka 1984). De Leede et al. (1982) compared the absorption profile of choline theophyllinate from a rectal osmotic delivery device with the profiles of an oral solution and of a suppository in 'Witepsol' HIS. Using the osmotic delivery system, in vitro and in vivo release were in good agreement, and the curves resembled those of a zero-order intravenous infusion. As might be expected from previous data oral absorption was rapid, t max being about 30 min, whereas the suppository demonstrated a rather slow uptake (tmax 2.Sh). The authors considered the osmotic delivery device to be a useful nonparenteral delivery system in clinical pharmacological studies in which steady-state drug concentrations are required (De Leede et al. 1982). Choline theophyllinate in hydrogels of hydroxyethyl methacrylate and ethylene glycol dimethacrylate as crosslinker also resulted in good agreement between in vitro and in vivo release profiles in male volunteers (De Leede et al. 1986). These formulations delivered
288mg of theophylline according to a matrix-type release pattern, resulting in near-constant plasma concentrations of about 2 mg/L. Hydrogels were suggested as promising rectal drug delivery systems with a predictable release profile, suitable for the administration of various drugs. Choline theophyllinate in aqueous solution was rectally administered to infants (age 14 to 44 months) with acute asthma (Kuzemko et al. 1985). Rectal doses of S.4 to 7.4 mg/kg resulted in plasma concentrations of 4. 7 to 11.2 mg/L and good clinical efficacy. This formulation was recommended as a suitable alternative to oral or inhalant medication. In an interesting report, Hooker et al. (1989) described the absorption profile of theophylline from colostomies in human subjects. After administration of a solution of aminophylline 300mg via the colon stoma, mean Cmax and t max were 6.2 mg/L and I.7h, respectively, indicating relatively rapid absorption. The extent of absorption was quite variable (between 19 and 123%), and the mean bioavailability amounted to 61 % relative to the oral solution. Three of 9 patients were unable to retain the solution administered via the colostomy, possibly because of local irritation, which is likely to contribute to the incomplete and variable colonic absorption. 3.7.2 Enprofylline The absorption of enprofylline, a bronchodilating xanthine drug which is poorly metabolised, was investigated in male volunteers after oral, intraduodenal and rectal delivery (Lunell et al. 1984). Rectal administration from an aqueous solution was somewhat slow compared with oral and duodenal uptake, with a t max of2.6h, O.Sh and 13 min, respectively. Oral absorption was complete, whereas urinary data indicated an absolute rectal bioavailability of about 89%.
3.8 Anticancer Agents 3.B.1 Tamoxifen The occurrence of nausea and vomiting in patients undergoing cancer chemotherapy with tamoxifen has stimulated research towards the de-
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velopment of a rectal formulation of that compound. Tukker et al. (1986) investigated the bioavailability of tamoxifen 40mg in 'Witepsol' H 15 and 'Suppocire AML' in healthy male volunteers. The drug was poorly and slowly absorbed from 'Witepsol' H 15 suppositories, resulting in a bioavailability of 20 to 40% relative to oral tablets. The 'Suppocire AML' displayed a worse performance, which may be related to the presence of lecithin, lowering the driving force for tamoxifen absorption. The low bioavailability from suppositories may be based on the lipophilicity of the drug, resulting in the observed poor in vitro release and in poor solubility in the rectal fluid (Tukker et al. 1986). No attempts were made to optimise the formulation by using a polyethylene glycol base, thus possibly enhancing in vitro drug release. The results should be interpreted in light of the fact that the suppositories were prepared from ground tablets, and the possible influence of tablet constituents on drug absorption was unclear.
3.B.2 Fluorouracil In a relatively small study, Takahashi et al. (1988) investigated the etTect of irradiation combined with rectal fluorouracil on the local recurrence of rectal carcinoma in cancer patients. Preoperative irradiation combined with 20 days' treatment with fluorouracil 100mg suppositories seemed to reduce lymph node metastases; however, further studies are necessary before the value of this approach to cancer therapy can be fully evaluated. 3.B.3 Medroxyprogesterone Acetate Medroxyprogesterone acetate is a progestational agent used in the treatment of metastatic breast cancer. As the oral availability of the drug is poor and erratic, Pannuti et al. (1986) investigated the applicability of medroxyprogesterone acetate 500mg in cocoa bu,tter suppositories. Rectal absorption was both slow and low, t max and Cmax being 4 to 8h and 0.8 to 3.3 J.tg/L, respectively, whereas the same dose administered orally showed values of 2h and 9.9 J.tg/L, respectively. It is conceivable that rectal absorption may be enhanced by employing a poly-
C/in. Pharmacokinet. 21 (2) 1991
ethylene glycol base, because the cocoa butter base may cause inetTective release of this lipophilic compound. 3.9 Drugs in Inflammatory Bowel Disease
3.9.1 Mesalazine and Derivatives Mesalazine is the active moiety of sulfasalazine, used in the treatment of inflammatory bowel disease. It is liberated from the orally administered parent drug in the colon by bacterial splitting of the azo bond (Brogden & Sorkin 1989; Jarnerot 1989). Since oral mesalazine is etTectively absorbed from the small intestine, the sulfapyridine part of sulfasalazine can be considered to be the carrier of mesalazine to the inflamed colon. As the adverse etTects of oral sulfasalazine are ascribed to the sulfapyridine moiety, etTorts have been undertaken to develop alternative colon-specific formulations of mesalazine without sulfapyridine, and with low systemic bioavailability, as reviewed by Jarnerot (1989) and by Brogden & Sorkin (1989). The use of enemas is a frequent approach (Hanauer 1989), and recently Sutherland et al. (1987) reported the etTectiveness of 60ml suspension enemas of mesalazine 4g as assessed in patients with ulcerative colitis of the distal colon. A suspension of mesalazine 4g in 100mi of vehicle, rectally administered to patients with ulcerative colitis, resulted in slow absorption, the Cmax of total drug being reached in 3 to 6h (Cam pieri et al. 1985). The drug was primarily present in plasma in its acetylated form and peak levels did not exceed 7 mg/L. Raising the enema volume to 200ml resulted in an increase in the amount absorbed, probably through an increase in the surface area available for absorption. Urinary data indicated incomplete colonic absorption of mesalazine, the fraction of the dose renally excreted in 24h not exceeding 37% (Cam pieri et al. 1985; Sutherland et al. 1987). With a suspension enema containing mesalazine 700mg similar results were obtained in patients with colitis and proctitis (Dew et al. 1983). Bondesen et al. (1988) compared the absorption characteristics of mesalazine 500mg in neutral phosphate butTer, instilled in the colon and rectum
Pharmacokinetics of Drugs Administered Rectally
of patients undergoing colonoscopy. Absorption appeared to be incomplete and variable; total amounts of drug excreted renally after colonic and rectal instillation were 20 to 4S% and II to 87%, respectively, of the administered dose. Another approach was followed by Allgayer et al. (1984), who investigated the absorption of solfasalazine from a 3g enema in patients with ulcerative colitis. Rectal absorption of the conjugate appeared to be faster, compared with the results cited above for unconjugated mesalazine, with a t max of 3h. On the other hand, concentrations of sulfasalazine and liberated sulfapyridine were lower after rectal administration than with oral tablets, which was considered a probable explanation for the low frequency of adverse effects from the rectal route (Allgayer et al. 1984). Sandberg-Gertzen et al. (1983) evaluated the rectal absorption profile of azodisal sodium, an azo bond-containing compound which may be split by colonic microorganisms into 2 mesalazine molecules. In healthy volunteers, an enema of azodisal sodium 2g in 100ml resulted in a mean Cmax of 2.1 mg/L of parent compound, reached in O.S to 2h, indicating relatively fast uptake. However, absorption was incomplete compared with the oral data, and I to 17% of the dose was excreted renally as parent drug and metabolites in 24h (SandbergGertzen et al. 1983). 3.9.2 Corticosteroids Rectal instillation of corticosteroids is now a well established approach in the treatment of inflammatory bowel disease. Since only a topical effect is intended, corticosteroids which show high efficacy and low systemic drug concentrations are preferred, in order to minimise adrenal suppression and other adverse effects inherent to steroid therapy. Therefore, corticosteroids and drug formulations displaying poor absorption or high firstpass metabolism are advisable. As outlined by Mulder et al. (1989), rectal prednisolone metasulfobenzoate, budesonide, tixocortol pivalate and beclomethasone diproprionate appear to interfere less with adrenocortical function, compared with hy-
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drocortisone acetate, prednisolone-21-phosphate and betamethasone. In clinical practice, steroid enemas prove to be difficult to retain, because of their large volume. Foam preparations appear to be better accepted, as described recently for a Sml hydrocortisone acetate foam (Neumann et al. 1989). In the latter trial, which was noncomparative, the foam was reported to be clinically effective, and systemic absorption was considered to be insignificant, judging from the lack of effect on serum cortisol levels. However, interpretation of these data is hazardous, because the procedure did not discriminate between exogenous (hydrocortisone) and endogenous cortisol. Cann and Holdsworth (1987) also investigated the systemic absorption of hydrocortisone acetate foam in patients with colitis, the endogenous production of cortisol being suppressed by dexamethasone. In that study, the foam, which contained a dose of hydrocortisone acetate 12Smg, resulted in a considerable rise in plasma cortisol levels, peak values of 82 to 370 ~gjL being reached in 4h. On the other hand, oral absorption of hydrocortisone acetate 20mg was faster, resulting in a t max ofO.Sh (Cann & Holdsworth 1987). The authors acknowledged the possibility of adrenal suppression and other adverse effects after application of the foam. Application of 20ml of a foam containing prednisolone metasulfobenzoate 20mg in patients with ulcerative colitis resulted in prednisolone concentrations in plasma and mucosal tissue comparable with those after an enema of prednisolone metasulfobenzoate 60mg in looml of vehicle (Rodrigues et al. 1987). It was suggested that the high concentration in foam resulted in more effective colonic absorption. A transient adrenal suppression was observed. Enemas containing prednisolone metasulfobenzoate proved to result in lower plasma prednisolone concentrations than obtained with prednisolone-21-phosphate (Lee et al. 1980; Rodrigues et al. 1987). 3.10 Cardiovascular Active Drugs 3.10.1 Nifedipine Rate-controlled rectal drug delivery of nifedipine I.S mgjh by an osmotic delivery device in healthy volunteers resulted in steady-state plasma
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concentrations of 14 to 27 jJ.g/L (Kleinbloesem et al. 1984). Interestingly, the low input rate resulted in a bl00d pressure-lowering effect without concurrent reflex tachycardia. In the latter study, the use of sodium salicylate 10 mg/ml and ethanol (1 mg/ml) was necessary to prepare an aqueous formulation of the lipophilic drug nifedipine 22 mg/ml. Use of a polyethylene glycol base is indicated when developing a preparation of nifedipine in the light of the above mentioned lipophilic character of this drug. Hence, Kurosawa et al. (1985) tested the absorption behaviour of nifedipine 10mg in healthy males, using a suppository base consisting of polyethylene glycols 400 and 4000. Rectal absorption was appreciable, resulting in a mean t max and Cmax of 1.75h and 68 jJ.g/L, respectively, whereas values of 0.78h and 110 jJ.g/L were found with oral soft gelatin capsules. The extent of absorption was comparable with both routes. In contrast to oral capsules, suppository administration significantly reduced systolic and diastolic blood pressure, without affecting the heart rate (fig. 10) [Kurosawa et al. 1985], confirming the results of Kleinbloesem et al. (1984). This pharmacokinetic and pharmacodynamic profile of rectal nifedipine was further confirmed in a later study by Kurosawa et al. (1987), which was performed in hypertension patients. The suppository was found to be useful in the management of hypertensive emergencies; application as a rectal sustained release formulation in long term hypertension treatment, as suggested by the authors, may be less practical. 3.10.2 Flecainide Acetate Lie-A-Huen and Kingma (1988) investigated the rectal absorption behaviour of flecainide acetate in a patient who responded poorly to oral flecainide, possibly because of a previous subtotal gastric resection. Flecainide acetate 200mg administered as a microenema showed rapid absorption (t max 1.5h) and complete absolute bioavailability. In addition, the absorption from a polyethylene glycol base was acceptable, t max and absolute bioavailability being 3.5h and 80%, respectively. Subsequent treatment with this suppository adequately controlled tachycardias in the patient. In contrast, absorption from
Clin. Pharmacokinet. 21 (2) 1991
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