Drug Dispositiotl

elln 1'1I3rmarok,nel 19(1): 11·31 . 1990

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Clinical Pharmacokinetics of Drugs Used in the Treatment of Gastrointestinal Diseases (Part 1) 1 Karstell Lallflisell. Lallrils S. Laursen and Jorgen Rask-Madsen ikpartmcnt of t.lcdlcal Gastroenterology. Odensc Um\'ersll) ilospltal. Odensc. and ikparlmcnt of Gamoenterolog) G. Blspo.'bJerg I-l ospnal. University o f Copenhagen. Copenhagen. IXnmark

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A C rna, of 13 "g,lL is required for 50% inhibition of tctragaslrin-stlmulaled gastric acid secrelion 111 healthy lolunteers (Miwa el a1. 1984). Plasma drug concentrations arc maintained at thiS lelel lor aboul 12 hours after an oral dose of famotldlne 40mg. 7 to 9 hours aner a 20mg dose and 5.5hoursanera 10mgdosc(Miv.aetai. 1984; Ryan el al. 1987). Howeler. blood conCenl ratlOnS bC'ar no consisten t relationship to doSl.w/1 /9 (I I IW(J

r-= sho\\ a \\ide Inlenndl\idual \anallOn ranging from 17to 710"gfL (Dekker & Relsma 1979: H:llnl1ton el al. 1983: T~ Igat el a!. 1982). Dail~ uri naT") e\CrellOn ofblsmulh has been rl'poned to be aboul 5-fold higher In patients .... Ith gaSlrlllS or duodenal ulcer (383 10 3787 ngf24h) than In h(·alth) subJecls (69 101415 ngf2-'h) after -' to I] .... ceks of trealment (Nwokolo c t a1. 1989). The rail' of renal e\Crellon drops by 2.6% per dar and Iht·n reaches stead}-stale 2 .... eds after wllhdra .... al of CBS trealment (L..:.'C 1981). Urme concentratIOns ma~ still be high at thiS time (24 to 250 "giL). suggestmg tlssm· accumulatIOn and slo .... mobilisatIOn (Hamilton t·t a1. 198]). Slgnlficantl~ Increa~(:d urinar~ blsmulh c\crction continues for atlcasl 12 \\eeks ((j:l\e~ t·t a!. 1989). -\t prl·scnl a .... ashoul period of H .... l't""ks IS recommended beI\>'('·l'n CBS cour'>l·s. No dala ha\(· t>.... en pubhshl'd on Ihe pharmacokinetics of CIlS 111 pallents .... lIh unpaired renal function. The reliance on ClK of an~ bismuth Ihal may be absorbed unpllCs. therefore. Iha\ Ihe usc of CBS In such pallenls should be dose!) moni\orell. Studies on Ihc effect of CBS on Ihe absorption of other drugs arc sparse. but coneurrenll} adminIstered calcIUm. Iron or lelrac}cline ma~ be decreascd (\\ agstaff l't al. 1988). -'.2 Sucralfalc Sucralfate IS a baSIC aluminium salt of sulphated sucrosc ..... hlch has Ix-cn sho .... n through controlled \nals to be effcctl\e In the trealment ofpepllc ulcers and In prewntmg recurrences (Brogden CI al. 1984). Hence. thiS drug rna) be conSidered as an al lerna\l\C 10 Ihe H1-receplor anlagonists In pePIiC acid disorders. Sucralfate is mInimall) absorbed after oral administration (Kinoshita el al. 1982) and on I) 0.5 to 2.2% of the dose IS rcco\ered in the uTine o\er a 4-da} penod (Gieslng l't a1. 1982). Nonelheless.

Ihe plasma concenlralions of alummium almost double (from -'96 to 771 "gfL) .... lth a regimen of sucralfate 19 4 times dall) fOf 2 da}s (Pal et a!. 1987). Moreo\er. Ihe unnaT) e:\:crl'lIon ofalummlum IS slgmficantl~ mcreascd dunng sucralfate treatment (Haram et al. 1987: Robertson et al. 1989). In patients \~lth uraemia. 10 particular. there IS an apl)reclablc s~stemlc absorptIOn of alurmnlum. and to .~ICIl~ has been reported (Leung el a1. 198]; Rolx!rtson ela1. 1989). Thus. caution should Ix- e.\ erclsed .... hen sucralfate IS administered to pallenls .... Ith Impaired renal funCllon. In ammal studies. 85 10 95% of a dose .... as located in the gastrolnlestmal traci (Brogden et al. (984). Ammal Siudies have sho .... n tha t simultaneous admlmstratlon of sucralfatc .... llh digo:\:in. pheny. tom. propranolol. qumldme or telT3qcline will result m a stallsllcall) sigmficanl reduCllon in Ihe bloa\'allabllll~ of phen~ lOin but nOI of the other agents. The blOavai labllll) ma) be reSlo red. howe\er. slmpl) b) separatmg Ihe adnllmstration of phen~toin from that ofsucralfate b) an interval of 2 hours (UCi et a1. 1982). ThiS mteraCllOn appears to be nons)stemlc m ongm. presumabl) resultmg from bmdmg .... llh sucralfate 10 the gastromtestmal tract The clinICal significance or these ammal studies lS )et to Ix- idenllfied. In humans. concurrent sueralfale admimstratlOn ma} decrease C but not the bloa\ allabiht) of mdomethacm. ketoprofen and napro.\en (Ana}a et al. 1986: Cadle el al. I 987a.b). These findings arc unhkely to be chnic· all) Important. Funher. no significant effecls of sucralfate ha\e Ix-en found on the dlsposlIlon of chlorpropam ide (Lclendre CI a!. 1986). digOXin (Glesing et a!. 1983). prl'dnlsone (Gambertoglio et a1. 1987) or theoph)lhne (Cantral el al. 1988). B) contrast. a decreased C (to one-third) of concomItantl) administered warfann during sucralfate treatment ma} Ix- cilmcall) Important. particular!) after sucfalfate .... lIhdrawal (Mungal1 el al. 1983).

5. A ntiulcer Agents, Others Finall). the managemenl of peplle aCid disorders rna) Include the use of antaCids 10 addition to \anous Invesllgalional drugs. among which Ihe

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o

HO/Cc:;:7:JC«XH' OH

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prostaglandin analogues have recently been 31> proved and marketed in a number of countries. 5.1 Antacids Antacids are basic compounds thaI neutralise acid in the gastric contents. They have been used through 2 millennia for abdominal 'dimcss', and formally by physicians for peptic ulcer treatment for more than a century and by the general public

for self-medication for a variety of symptoms. Indeed. many patients would neither consider them 10 be medicine. nor declare them as such when Questioned about concomitant medication. Since the early 1970s, high dose antacid regimens have been proved to provide healing and symptom relief in patients with peptic ulcers comparable to that of an H2-rcx:eplor antagonist. in controlled clinical trials (Berstad & Weberg 1986). The antacids vary in the extent to which they are absorbed. Unneutralised sodium bicarbonate and sodium citrate are completely absorbed and cause transient metabolic alkalosis. By contrast aluminium. calcium and magnesium ions are incomplctcly absorbed. and antacids containing these metals do not aller the acid-base balance to the extent that sodium bicarbonate and sodi um citrate do. It is beyond the scope of the present review to discuss the basic pharmacokinetic features of antacids (see. for example. Harvey 1985: Ivanovich et al . 1967). A number of drug interactions with antacids have been described (reviewed by. among othcrs. D·Arcy & McEl nay 1987; Hurwitz 1977): e.g. ampicillin. aspirin. atenolol. betamethasone. chlordiazepoxide. chloroquine. chlorpheniramine. chlorpromazine. cimetidine. ciprofloxacin . dexamethasone. diazepam. dicoumarol. diflunisal. digoxin. disulfiram. estramustine. famotidinc. indo-

methacin. iron. Isoniazid. keloconazole. ketoprofen. levodopa. lithium. metoprolol. mexiletine. na· proxcn . nitrofurantoin. nizatidinc. oral contraceptivcs. pencillamine. pentobarbi tal . phenothiazines. phenytoin. prednisone. procainamide. propranolol. pyrimethamine. quinidine. quinine. ranitldine. sulphonamides. tetracyclines. theophylline. valproic acid. and warfarin). The mechanisms of interactions involve an alteration of intragastric pH (giving rise to an ahered dissolution rate of drug formulation. changed drug ionisation and modi· fied absorption patterns). adsorption of drug. or formation of poorly soluble salts or complexes. Interactions with antacids may also involve changes in gastric emptying and urinary pH. Many of the repons are animal experiments. uncontrolled single dose studies or anecdotal evidence in humans. Others are based solclyon in I';tro evidence. In the majority of cases the clinical significance of these interactions is doubtful. but potenlially Imponant interactions with antacids have been suggested for ferrous sulphate, isoniazid and tetracyclincs (D'Arcy & McElnay 1987). S.2 Prostaglandin Analogues Synthctic prostaglandin analogues of the E se· ries offer yet anothcr approach to the mcdical treatmcnt of peptiC ulccr dIsease. However, any superiority of these drugs. which might be expeeted by their addressing both mucosal aggressive and defcnsive factors, has not been demonstrated when compared with the H2-rcccptor antagonists (lauritsen et al. 1989). Enprostil Enprostil (fig. 7) is a synthetic analogue of dinoprostone (prostaglandin E2) (Goa & Monk 1987). Its chemical name is (+)-4.5-didehrdro-I6-phen-

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I'harmacolmetlCS of GastrOlntestmal Drugs

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6. A ntiemetics and Prokinetics

H,H-QCCJ.HH.CH,.CH,."C,H,. OCH, Fig. 9. Structura l formula of m,·toclopram.de

oxy-w-tetranor-prostaglandln E!. Published data descrlbmg the pharmacoklnctlc properties of enprOS1l1 arc limited. although an HPLC assay has been described by Kcnlcy et OIL (1986). Thc Cma~ aftcr a dose of enprostil I "glkg IS attained "Ithm 0.5 10 1.0 hours. The I., is aboul 34 hours: 53% of the dose IS recovered in Ihe Urine and 34% in the faeccs (Stanski et al. 1982). Enproslil docs nOI appear 10 affect the dIsposition of propranolol (ReIlly el al. 1986) or thcoph) lItne(Bynum & Gross 1986). MlsoprOSlO1 MisoproslOl (fig. 8) IS a synthetic analogue of alprosladll (prostaglandtn Ed [Monk & Cltssold 1987). lIs chemical name IS (+)( 16RS)-15-deo\)16-hydro'(y-l 6-mclh) l-prOSlaglandln E I. Folio" 109 oral admInistratIOn. mlsoproSlO1 is rapIdly absorbed and de-cstcrified to liS acid form. wh ich is equipolent wllh misoprostol 10 the inhibition of aCId SC('rellon In Isolated call1ne panetal cells (Tsal et al. 1986). Cma \ (0.3 to 2.0 "gIL determined by RIA or thin-layer chromatography (TLC) after a 200"g dose and 0.7 10 4.0 JJglL after a 400JJg dose) is reached in 0.5 to 1.0 hour (Allan et OIL 1983: Lcese et OIL 1986). Mlsoprostolls about 85% bound to serum prolelns (Schocnhard et al. 1985). In rat gastrointestinal. hepatic and renal tissues the concentrat ions of radlolabelled misoprostol were 6 to 73 lImes higher Ihan in plasma, whereas the concenlrations In all other tissues were lower Ihan In plasma (Schocnhard et a1. 1985). Following deesterification the~ is .B-oxidallon of the a side chain. ...-oxidalion of the .B side chain. and reducl ion 10 prostaglandin F analogues (Schocnhard el OIl. 1985). Renal excretion accounlS for approximately 65% of Ihe eliminalion of a single oral dose ofmisoproslol 100 JJg wilhm 24 hours and 15% IS excreted In Ihe faeccs. T he \t" of misoprostol IS abou l 1.5 hours (Allan el a1. 1983: Leese el al. 1986: Schocnhard et OIL 1985).

6. 1 Meloclopramide Meloclopramide (fig. 9) is 4-amino-5-chloro-S11-(dleth) I-am 1110 ) elhy IJ-l-methox ybcnzarn ide monohydrochlonde rnonoh)drate. It antagonises the elTect of dopamine 111 Ihe cenlral nervous syslem and gastrointestinal smooth muscles. Furthermore. II augments acelylcholine release and senSI\lSCS the muscannic receptors of gaslromleslmal smOOlh muscles. \\.hlch coordinate gaslroduodenal motor func tion. Clinically. Ihe drug is used primarily as an anliemelic and for Irealmenl of gUI mOliltly disorders (Alblbl & McCallum 1983: Harringlon el al . 1983: Pinder el al. 1976: Schulze-Dclrieu 1981). Concentralions of metocloprarnide 10 biological nuids have been assessed b). for example. gas ch romalograph)-mass spec trome try (GCMS) [Baleman el al. 1978b). HPLC (Baleman el al. 1981 : Blocl el a1. 1981: BT)son et al. 1984: GralTner el a1. 1979: Siordal et al. 1986: Takahashi et al. 1987: Teng et al. 1977). gas-liquid chromaIOgraphy (GLe) JRoss-Lce el aL 1980: Tam & Axelson 1978: Tam el OIL 1979). liquid chromatograph y (LC) IGu)on et al. 1987) and RIA (Dc Villiers el al. 1987). 6. /. / Basic Pharmacoklnellc Propl'rIU!S Absorpllon Meloclopramlde IS rapidly absorbed after oral admmiSlrallon. Cma~ (on average. 40 "gi L after a dose of rneloclopramlde lOmg and 80 "giL after a 10mg dose) are aHamed Y,Jlhm 1 hour (Bateman et al. 1980: GralTner et al. 1979: Ross-Lee el al. 1981). The C ma \ rna) show considerable mterindividual vanation because offirsl-pass melaboltsm (Baleman el a1. 1979. 1980: Ross-Lee el OIL 1981). The bloavallabihty also shows "Ide mtenndividual vanallon (32 10 97'1b) (Baleman el a1. 19801: 11 is lOwer after rectal admmlstrallon (53% versus 76% in I crossover study). wilh C m:u, aHamed a fter I to 3 hours and a sccond peak between 4 and 8 hours (Block el al. 1981).

C!tn

Distribution A 2-compartmcnt modcl has been fou nd to describe thc disposi tion of intravcnous mctoclopramidc (Batcman ct al. 1980). The Vd of thc drug is 2 to 4 /kg l (Bateman ct al. 1978b. 1980: Block et al. 198 1: Graffneret al. 1979: Ross-Lee ct al. 198 1). indicating an extensive extravascular distribution. Studies on its distribu tion in animals have revealed the highest concentrations of metoclopramidc in the intestinal mucosa.. the li ver and biliary tract. and the salivary glands. In Ihe cenlral nervous system meloclopramide waslocalcd in the area postrema that contains t he chemoreceplor Irigger zone for vomit ing i n humans (Pinder el al. 1976). Metoclopramide is about 40% bound to plasma proteins. mainly ai-acid glycoprotein (Webb et al. 1986). It readily en ters breast milk (Kauppila et al. 1983: Lewis el al. 1980). Elimination Abou l 80% of an oral dose of metoclopramide is excreted in the urine within 24 hours. eilher as unchanged drug (20%) or as sulphate and glucuronide conjugates (Batcman el al. 1980: Graffner et al. 1979: Teng et a1. 1977). A major melabolitc is N-4-sulphate of mctoclopramide. which accounts for 32 and 40% of thc dose recovered after in travenous and oral administration . respecti vely (Ba teman ct al. 1980). Other metabolites are Ihe N-4-glucuronide (less than 2% of the dose) and the side chai n prod uct. 4-ammo-5-chloro-2-methoxybenzamido-acet ic acid (Bateman 1983). The Cl of metoclopramide is about 40 10 50 L/ h. thus approximat ing li ver plasma flow (Bateman el al. 1978b. 1980: GrafTner et al. 1979; Ross-Lee et al. 198 1). The ClM. accounlS for 20% of the CL. suggesting Ihat the clearance is limited by li ver blood now. rather than by liver metabolic capacity. The \'/: of metoclopramide is 2.5 to 5 hours in patients with no rmal renal function (Baleman el al. 1978b. 1980: Graffner et a1. 1979; Ross-Lee et al. 1981). Single dose studies have suggested a dosedependent elimination of metoclopramide (8.1teman et al. 1979. 1980; Graffner et al. 1979). but more recenl studies have fai led to demonstrale dose

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dependent pharmacoki net ics wilh oral doses up to lOOmg (Bateman 1983: Harrington et al. 1983). 6.1.2I:.ffec/ of Age alld Disease 011 Pharmacokinetics In children the pharmacokinellcs of metoclopramide is Similar to that observed in adults (Baleman et al. 1983). The t'h of metoclopramide is about 9 to 19 hours. and elR '"" 5 to 17 lIh in patients with moderate to severe renal impairment (Bateman el al. 1981: Lehmann et al. 1985). The change in the val ue of e l M. cannot entirely be explained by Ihe reduction in ClM. in these palients. and suggcsts ei lher renal metabolism of metoclopramide. as in rats (Tam el al. 1981). or enterohepatic circulation of Ihe sulphate conjugate (Arita et al. 1970: Baleman 1978). Since ex trapyramidal side effects occur more commonly in patients wi th renal failure (Bateman & Davies 1979: Caralps 1979). a 50 106Mb reductIOn oflhe dosage is envisaged in patients wilh severely impaired renal function (Baleman et al. 198 1: lehmann et al. 1985). In ralS with hepatic failure a 3-fold incrcase occurs in the I,,, ofmetoclopramidc (Tam el al . 1981). but such dala arc difficult to ex trapolate to humans. In patients with cirrhosis Ihe bioa vai labili ty of metoclopramide is increased (82 versus 60%). but the AUe is similar to thai In a control group (Hellstern el al. 1987). Dosage adjustmenls may be necessary. Metoclopramide disposition in diabetic palienls wilh gaslroparesis is similar to that observed in heallhy subjects (O'Connell et al. 1987). 6.1.3 Drug ImeraclIon POlemial Meloclopramide enhances gastric emptying and may Ihereby alter the absorption of various drugs. By eontrast. there is no evidence that meloclopramide affects either urinary or biliary excrellon of olher drugs. Metoclopramide has been reponed to decrease the t'" of aspirin (Pindcr el al. 1976). cimetidi ne (Guglercl at. 198 1a; KanlO el al. 1981). cycJosporine (Wadhwa el al. 1987). diazepam (Ga mble e lal. 1976). digoxin (Johnson etal. 1984a). 1cvodopa (Pinder el al. 1976). mexiletine (Wing el

I'harma(,o~,nl't'('s

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of GastrOlntl'stlnal Drugs

al. 1980). morphine (Manara et ai. 1988). paracet:1mol (Crome el al. 1981). plvamplcillin (Pinder el al. 1976). t('uac}chne (Pinder el al. 1976) and 101fenam lC aCid (Tokola et ai. 1982). However. increased C,lla, occurred onl~ wilh asplnn (Ross-Lee ~'t al. 198::!). c~closporln (Wadh\la et al. 1987). dia/cpam (Gamble e\ al. 1976) and Ie\odopa (Pinder el al. 1976). With dlgo.\1n a sllghl decrease in Ihe \l lC and bioa,ailahiht~ ma~ be Ihe resull ofa decreased effect ile lime for absorption (Johnson et al. I 98-1a: Kirch et al. 1986a). A sligh I decrease in the AUC of quinidine ma) also occur in patients receiving concurrent metoclopramide (Vuen et al. 1987). The laller drug may also accelerate Ihe absorp\lon and raise Ihe plasma concenlrations of alcohol (Pinder et a1. 1976). whereas the pharmacoklnellcs of ate nolo I (Reg~rdh et a1. 1981). isoni;;zid (Pinder el al. 1976). lorazepam (Diamond 1978). mlsomdalOle (Williams el al. 1983). propranolol (Charles c\ al. 1981) and Iheoph~ 1Il1le (Sleeves et al. 1982) are largi.'!) unchanged. Fell of the abol e findlllgs. If an~. appear 10 lx' cllIlicall~ Important. 6. 1..1 RdlJlu}//slllp

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alld PharmaCO(/n1(l1l1lc.1 There is no evidence of a direct link between Ihe plasma concenlratlons of metoclopramide and liS therapcu\lc effects (B:m'man 1983: O'Connei el al. 1987: Strum ct a1. 1983). It has been suggesled that the IOxic em'Cls of metoclopramide. e.g. d)sklnaesia and akathlsia, or lack of consislen\ pharmacological effeCls belween Individuals. ma) be related to ihe "ide interlndi, Idual variation in C after oral administration. In particular as a result oflariabiht) in first-pass melabolism (Bateman & Dalles 1979: Bateman el al. 1978a. 1979. 1980). 6.2 Dompcridone Dompcridone (rig. 10) [5-chloro-l-I-[3-(2.3-d1·

Fig. 10. Slruc\Ural formula of dompcndonc propert ies si milar 10 those of meloclopramide. but docs nOI readily cross the blood-brain barrier. Clin ically. the drug is used as an anliemelic and for trealment of gut motilily disord~rs (Brogden el al. 1982a: Champion 1988). The concentralions o f domperidone and its metabolites in biological fluids have been assessed by RIA (HeykanlS CI al. 198 1a) and HPLC (Meuldermans el al. 1981). 6.2. J Basic !'harmacokll1l'tic Prop('rtl(,S

AbsorptIOn Dompcridone C mn of about 20 and 80 ",giL is attained approxlmalely O.S 10 I hour after oral administration of doses of 20 and 60mg. respectilcl~ (He)kan IS et al. 1981a: Huang el al. 1986) and concentrations of approximately 20 ",giL arc allained I 10 2 hours after rectal administration of a 60mg dose (Heykants el a1. 198Ia). While Ihe bioavailability of Inlramuscularly administered dompcridone is aboul 90%. that of oral and rcrtal drug is onl~ 12 to 18% (Heykants el al. 198I a). which suggests extensive first-pass metabolism because less than 10% IS excreled unchanged in the faeces (Meuldermans et al. 1981). The bioa l'ailabi lity is increased (10 abo ul 24%) if the drug is administered 1.5 hours after a meal (HeykanlS ct al. 198Ia). but it is decreased by prior admin istration of clmetldine (Brogden ('t a1. 1982a). No drug accumulal ion occu rs dunng repeat dosing (HulZlng el al. [980).

h~ dro-2-oxo-1 H-ben zimidazole-I-~ I)propyl J-4·pi·

pend in) l-I.3-di hydro-2H.benzimidazole-2-oneJ. is a potent periphcral dopamlnc an tagonist. which acts al the chemoreceplOr trigger zone on Ihe floor of the fourth brain \'enlnele and on dopamine rerepIOrs in the gut. It has antiemelic and prokine\lc

Di stribution A 3-compart ment model has be~n found to describe the disposition of intravenous dompendone (Heykanlsel al. 198Ia). The Vd isabout51O 6 L/ kg ( Heykanls 1'1 al. 1981a: Huang el al. 1986). in-

0 ", PhafmaroJ.lflrt 19 (I )

30

dicating ex-Iensive distribution. No data on the distribu tion in humans have been published, but studies in rats have shown wide distribution in body tissues except the central nervous system. where on ly low concentrations occurred. Small amoun ts crossed the placenta and were excreted into breast milk (Heykanls el 31. 1981b; Hofmeyr et al. 1985: Michels et al. 1981). The binding to plasma proteins is about 92%. Elimi nation The C Lof domperidonc is 30 \0 40 L/ h (Hey· kanls et al. 1981a; Huang e t al. 1986). The C LR of unchanged drug is negligible. Dompcridone undergoes rapid and extensive biotransformation by hydroxylation and oxidative N-dealkylation, yielding hydroxy-domperidone and 2.3-dihydroxy.2-oxoI H-benzimidazole- I-propionic acid, rcspei:tively (Meuldermans et al. 1981). Thus. less than 2% of the administered domperidone is excreted unchanged in the urine, and less than 10% in the faeces. After oral administration approximately 30% of total drug is excreted in the urine and 60% in the faeces. The major proportion in the urine is recovered as glucuronide conjugates o f the metabo lite fo rmed by ox idative N-dealkylation. The t\l1 of domperidone is 7 to 16hours in healthy subjects (Heykants et al. 1981a: Huang et a\. 1986). 6.1.2 l;.1Ject of Age and Disease on I'harmacokinetics In patients with severe renal impairnlent (serum creatinine > 530 .l'mol/L), the t\l1 of domperidone is prolonged (up to 21 bours). Since the CLR is small compared with Cl.. accumulation does not occur in patIents WIth renal dysfunction (Brogden el al. I982a). 6.2.3 Drug Interaction Potenlial The drug interaction potential for domperidone would be eXpei:ted to be si milar to that of metoc10pramide (sectio n 6.1.3) but, at present. this is unconfirmed.

1m

6.2.4 Relationship Bl'tll'N'n Pharmacokm('/ ICS and Pharmacodynamics There is no evidence of a d irect link between plasma concentrations of domperidone and Its therapeutic effecls (Brogden et al. 1982b: Champion 1988).

6.3 Cisapride Cisapride (fig. II) is (+/ -)