Influence of lansoprazole treatment diazepam plasma concentrations The possible influence of long-term treatment with lansoprazole on the single-dose pharmacokinetics of diazepam was investigated in 12 healthy male volunteers. In this double-blind randomized crossover study, 60 mg lansoprawle or placebo was administered once daily for 10 days. One hour after administration on day 7, 0.1 mgkg diazepam was administered intravenously, and blood was collected up to 96 hours after the injection for plasma diazepam and desmethyldiazepam measurement. During the placebo session, the plasma elimination half-life, clearance, and volume of distribution of diazepam were 26.0 2 1.6 hours, 22.5 & 1.1 ml/hrkg, and 0.82 & 0.04 Lkg, respectively. These parameters were not significantly different during the lansoprazole session. The mean plasma concentrations of desmethyldiazepam were similar in both sessions. These lindings illustrate that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam. (CLINPHARMACOL THER 1992;52:458-63.)
Romain A. Lefebvre, MD, PhD, Bernard Flouvat, PhD, Sara Karolac-Tamisier, PhD, Emmanuel Moerman, PhD, and Eric Van Ganse, MD Gent and Brussels, Behiurn, and Boulogne, France Lansoprazole is a member of a new class of gastric acid antisecretory drugs, acting by inhibition of the ~ ) the parietal gastric proton pump ( H + , K + - A T P ~ Sin cells.'32 Its effectiveness in the treatment of patients with duodenal ulcers has been established.' A oncedaily dose of 30 or 60 mg is required.3%4Lansoprazole is a substituted benzimidazole. Like the prototype e,~ is drug of this new class, ~ m e ~ r a z o l lansoprazole extensively biotransforrned, mainly by oxidative metabolism. The main metabolites are the sulfone, the sulfide, and hydroxylanzoprazole; the sulfone and the sulfide are also hydroxylated. Urinary elimination, mainly as metabolites, represents only about 25% of ~ - omeprazole, ~ it has been shown that its the d o ~ e . For binding to hepatic cytochrome P450 can inhibit the oxidative metabolism of a limited series of drugs, that is, drugs metabolized by the cytochrome P450 enzyme subfamily IIC.' Diazepam belongs to this group; a re-
From the Heymans Institute of Pharmacology, University of Gent, Gent; the Laboratory of Toxicology and Pharmacokinetics, A. Par6 Hospital, Boulogne-Billancourt; and Roussel Uclaf, Brussels. Received for publication Jan. 28, 1992; accepted June 30, 1992. Supported by Roussel Uclaf, Brussels, Belgium. Reprint requests: Romain A. Lefebvre, MD, PhD, Heymans Institute of Pharmacology, University of Gent, De Pintelaan 185, B-9000 Gent, Belgium. 13/1/40715
duced clearance of diazepam during long-term treatment with omeprazole was shown in three studies, 10-12 The aim of this investigation was to study the possible influence of therapeutic doses of lansoprazole on the pharmacokinetics of a single intravenous dose of diazepam in 12 healthy male volunteers.
METHODS Subjects and study design. White male subjects were judged to be healthy on the basis of past medical histories, physical examinations, electrocardiograms, and laboratory screenings (complete blood cell count with differential, routine blood chemistry, and urinanalyses) 2 weeks before the start of the study. The study was performed in accordance with the Declaration of Helsinki, as revised in Hong Kong, and approved by the Medical Ethics Committee of the University Hospital (Gent, Belgium). Written informed consent was obtained before the study. The study was organized as a placebo-controlled, double-blind randomized crossover study with two treatment periods of 10 days, separated by a washout period of 18 days. Eighteen volunteers were included in the study. Five were excluded because of protocol violations during the washout period. One volunteer stopped the intake of study medication on day 4 of the first treatment period because of diarrhea; "unblinding" at the end of the study revealed that he had been taking placebo. Twelve volunteers (age range, 22 to
VOLUME 52 NUMBER 5
28 years; weight range, 62 to 94 kg; height range, 174 to 201 cm) finished the two treatment periods, and the findings from these subjects were evaluated. Seven of these volunteers started with lansoprazole and five with placebo. Two capsules of 30 mg lansoprazole or placebo were taken once daily before breakfast around 8 A M . On day 7, at the laboratory after they had fasted for at least 8 hours, the subjects took the dose of lansoprazole or placebo with 100 ml water. One hour after intake, diazepam (0.1 mglkg) was administered intravenously to each subject in five fractions (5 seconds per fraction) at 1-minute intervals by way of a cannula in an antecubital vein. The volunteers remained in a semisupine position for 2 hours after the administration of diazepam. Blood was collected in heparinized tubes before the intake of lansoprazole or placebo (lansoprazole blank), before the intravenous injection of diazepam (diazepam blank), and 5 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 24, 3 6 , 4 8 , 6 0 , 72, 84, and 96 hours after the injection of diazepam (start of the injection of the first fraction of diazepam is time 0). Up to 12 hours, two blood samples (5 ml for diazepam and 6 ml for lansoprazole) were obtained by way of a cannula in an antecubital vein in the arm contralateral of the injection site; the samples for lansoprazole were collected in ice-chilled tubes. Samples were centrifuged and the plasma stored at -20" C (diazepam) or -60" C (lansoprazole) until assay. The subjects received standardized meals 2, 6, and 10 hours after the administration of diazepam. The same laboratory screen as performed before the study was done at the end of the study. All other medication was prohibited from 2 days before the start to the end of the study. Two volunteers were light smokers (fewer than five cigarettes a day) and were asked to refrain from smoking during the study. Moderate alcohol intake (maximum, 2 glasses per day) was allowed except for days 7 to 11 of each treatment period. Analytic methods. Plasma concentrations of diazepam and desmethyldiazepam were determined by HPLC with slight modifications from previously described method^.'".'^ Camazepam was used as the internal standard. The chromatographic system consisted of a Waters 510 HPLC pump and a Waters 484 variable wavelength monitor set at 240 nm (Waters Chromatography Div., Millipore, Milford, Mass.) The column was a RoSil C-18HL 5 pm (250 X 4.6 mm, Bio-Rad Laboratories, Eke, Belgium). The chromatograms were recorded on a Waters data and chromatography system with Baseline 8 10 chromatography software (Waters Chromatography Div., Millipore). The mobile phase consisted of 0.1 mollL
Lansoprazole-diazepam noninteraction 459 phosphate buffer (pH 2.7), methanol and acetonitrile (575:30:395), and 100 pl triethanolamineiL. The flow rate was 1.6 mllmin. Plasma samples with high benzodiazepine concentrations were diluted with water at a ratio of 1 :2 or 1 :5 . The detection limit was 5 ngl ml. The between-run accuracy for a plasma pool spiked with 20 and 100 nglml diazepam was 107% and 10 1 %, respectively, with a relative SD of 9.6% and 3.2% ( n = 12). Reference diazepam and desmethyldiazepam were obtained from Roche (Brussels, Belgium); camazepam was obtained from Sintesa (Brussels, Belgium). Plasma lansoprazole was determined as described p r e v i o u ~ l y . The ' ~ detection limit was 3 nglml and the between-run precision for plasma samples spiked with 8, 80, 400, and 2000 nglml was 18.1%, 6.1 %, 5.0%, and 3.8%, respectively (n = 12). Data analysis. The plasma concentration- time profile of diazepam was analyzed with use of the NONLIN computer program ~ u l t i (two-compartmental l~ model); the intravenous administration of diazepam was considered to be a bolus injection. From A, (Y, B, and p , the area under the plasma concentration-time curve to infinity (AUC) was determined. The systemic clearance (CL) was then obtained from DIAUC, in which D is dose. The volume of distribution (V,,,,) during the terminal phase was determined from CLIP, and the half-life of the terminal phase (t,,?) was determined from 0.693lp, in which P is the terminal elimination rate constant. The AUC(0-96) for the metabolite desmethyldiazepam was determined by the trapezoidal method, and its ratio to the AUC(0-96) of diazepam (also determined by the trapezoidal method) was calculated. The AUC of lansoprazole was determined by the trapezoidal method up to the last quantifiable concentration and extrapolated to infinity by use of this last concentration and the apparent elimination rate constant (k,), which was determined by nonlinear regression analysis of the plasma concentrations during the terminal phase. The apparent oral clearance (CLIF), V,,$F, and t,,, were then determined as described for diazepam. Statistical analysis. The findings are given as mean values ? SEM. Statistical analysis was done by means of a two-way ANOVA (subjects and treatments). p Values less than 0.05 were considered to be statistically significant. Standard confidence intervals at 5% were also calculated.
RESULTS All volunteers reported some dizziness, sleepiness, fatigue, or concentration problems during the hours
CLIN PHARMACOL THER NOVEMBER 1992
460 Lefebvre et al.
0
24
48
72
96
72
96
Hours
0
24
48 Hours
Fig. 1. Mean (and SEM) plasma concentrations of diazepam and desmethyldiazepam after single intravenous administration of 0.1 mglkg diazepam, after 7 days of oral treatment with lansoprazole (solid circles) or placebo (open circles).
after the administration of diazepam, except for one volunteer in the placebo session. Two volunteers reported diarrhea under lansoprazole; one reported diarrhea, two reported more frequent defecation and one smoother defecation during placebo administration. The mean plasma diazepam and desmethyldiazepam concentration-time profiles during the lansoprazole and placebo treatment periods are shown in Fig. 1; the pharmacokinetic parameters are given in Table I. No consistent difference in the plasma diazepam concentration-time profile was seen between the lansoprazole and the placebo sessions. The AUC of diazepam during lansoprazole treatment was higher than that
during placebo treatment in eight volunteers but lower in the other four volunteers. The pharmacokinetic parameters of diazepam in the two sessions did not differ significantly. The AUC(0-96) of desmethyldiazepam in the placebo session was 2455.7 '- 161.7 ng - hrlml; the ratio to the AUC(0-96) of diazepam was 0.56 -+ 0.05. In the lansoprazole session, these values were 2379.6 ? 127.0 ng . hrlml and 0.50 2 0.03, respectively, and they were not significantly different from those in the placebo session. The plasma contained a quantifiable amount of lansoprazole up to 9 hours after its administration in eight volunteers, up to 11 hours in three volunteers, and up
VOLUME 52 NUMBER 5
Lansoprazole-diazepam noninteraction 46 1
Fig. 2. Mean (and SEM) plasma concentrations of lansoprazole on the seventh day of oral treatment with 60 mg lansoprazole once daily.
Table I. Pharmacokinetic parameters for single intravenous diazepam (0.1 mglkg) after 1 week of oral placebo or 60 mg lansoprazole AUC (ng . hrlml) Placebo Lansoprazole
Mean SEM Minimum Maximum Confidence interval (%)
4574.1 232.6 3435.4 5775.2
5125.9 317.9 3403.6 7382.0 99- 123
-
CL (mllhrlkg) Placebo Lansoprazole
22.5 1.1 17.3 29.1 -
20.4 1.3 13.5 29.4 81-100
Placebo
Lansoprazole
Placebo
26.0 1.6 18.8 33.8
28.8 2.1 17.3 45.6 98- 123
0.82 0.04 0.68 1.10
-
AUC, Area under the plasma concentration-time curve; CL, total body clearance; tv2, half-life; V,,,,
to 13 hours in one volunteer. The mean plasma lansoprazole concentration- time profile is given in Fig. 2. The maximal plasma concentration of 1453.3 2 151.6 nglml was reached at 1.5 0.1 hour after administration; the apparent plasma elimination tlI2 was 1.0 2 0.04 hour. The CLIF and V,$F were 18.3 2.0 Llhr and 25.5 + 2.3 L, respectively.
*
*
DISCUSSION This study shows that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the kinetics of diazepam. The pharmacokinetic parameters for diazepam during the placebo session were similar to those reported in previous studies. ''-I2 The interindividual variation in the CL of diazepam is large.17 It has been suggested that the metabolism of diazepam in white subjects is related to the mephenytoin hydroxylation phenotype; that is, poor metabolizers of S-mephenytoin show slow diazepam metabo-
v,,,,
t1v2 (hr)
-
@/kg) Lunsopruzole
0.82 0.06 0.66 1.45 91-109
volume of distribution.
lism.I8 The incidence of poor S-mephenytoin metabolism in white subjects is 3% to 5%.14 The plasma tY2of diazepam in our study ranged from 18.8 to 33.8 hours; these figures are clearly below the values (69 to 101 hours) reported in poor metabolizers of S-mephenytoinI8; it therefore seems unlikely that one of the volunteers studied was a slow metabolizer of diazepam. The pharmacokinetics of lansoprazole showed a large intersubject variability, as observed in previous studies. The CLIF, VareaIF, and tlI2 were similar to . ~ those reported previously (Delhotal-Landes et a ~and Flouvat B , Delhotal-Landes B , Cournot A , Dellatolas B. Unpublished data, 1992.) In contrast to what has been observed for omepra~ o l e , ' ~ long-term -'~ treatment with lansoprazole did not influence the metabolism of diazepam. It has been shown that slow metabolizers of omeprazole are also slow metabolizers of diazepam; in this small sub-
462 Lefebwe e t al. group, omeprazole does not interact with diazepam." As described above, our study did not contain slow metabolizers of diazepam, so this is not the explanation for the absence of an interaction. Blood was collected for diazepam and desmethyldiazepam analysis up to 96 hours after administration. This period, corresponding to at least three times the plasma t,,> of diazepam in most cases, should be sufficient to observe an inhibitory influence of lansoprazole on the metabolism of diazepam. In the study of Gugler and ense en," the impairment of diazepam metabolism by omeprazole was clearly observed with a sampling period of only 72 hours after administration. The intake of placebo or lansoprazole was controlled only on the seventh day of the treatment period, when diazepam was also administered; the compliance of the volunteers was further checked by pill count in the drug reservoir on the mornings of days 7 and 11. It seems unlikely that poor compliance can explain the lack of effect of lansoprazole on the metabolism of diazepam because prolongation of the effect of diazepam was observed in rats after single dosing of lans~prazole.'~ In vitro, in rat liver microsomes, lansoprazole was shown to be twice as potent than omeprazole for inhibition of three cytochrome P450 dependent enzymes, that is, dealkylation of 7-ethoxycoumarin, N-demethylation of ethylmorphine, and hydroxylation of lonazolac.20 However, these enzymes belong to the rat cytochrome IIB subfamily, whereas diazepam in humans is metabolized by the cytochrome IIC subfamily.y Still, in rats in vivo it was shown that the effect of diazepam is prolonged after treatment with omeprazole and l a n s o p r a z ~ l e . ' Omeprazole ~~~~ thus inhibits the metabolism of diazepam in both rats and humans, whereas lansoprazole does so only in rats, because our study in humans did not show an interference. This illustrates the difficulties of extrapolating animal data to humans; it should be kept in mind that different species have developed their own specialized cytochrome P450 isozymes. Interaction studies should thus be performed in humans before conclusions on possible clinical advantages of a particular drug can be put forward. Omeprazole and lansoprazole are both substituted benzimidazoles, containing the imidazole ring of cimetidine. This ring structure is thought to be responsible for the inhibitory effect of cimetidine on various drug-metabolizing enzymes in the liver.22 The possible pharmacokinetic interaction with omeprazole was already studied for various drugs, showing that the number of significant interactions with omeprazole is clearly less pronounced than with cimetidine. For ex-
C1.N PHARMACOL THEK NO\'EMRER 1992
ample, for theophylline, warfarin, and phenytoin, which show clinically important interactions with cimetidine, no inhibition or no clinically relevant inhibition of metabolism was observed with ~ m e ~ r a z o l e . ~ The number of enzymes inhibited by omeprazole is thus probably limited. Omeprazole nevertheless clearly impairs the metabolism of diazepam in humans, whereas our study shows that lansoprazole does not. We have no explanation for this difference because both drugs seem to interfere with diazepam metabolism in rats. In view of the wide therapeutic range of diazepam, the degree of inhibition of diazepam metabolism by omeprazole does not seem to be pronounced enough to be clinically r e l e ~ a n t . " ~ ' ~ In conclusion, this study shows that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.
References 1. Nagaya H, Satoh H, Kubo K, Maki Y. Possible mechanism for the inhibition of gastric (H+,K+)adenosine triphosphatase by the proton pump inhibitor AG-1749. J Pharmacol Exp Ther 1989;248:799-805. 2. Satoh H, Inatoni N, Nagaya H, et al. Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs and rats. J Pharmacol Exp Ther l989;248:806-15. 3. Licht H, Andrieu J, Bognel JC, et al. Lansoprazole versus ranitidine dans le traitement des ulceres duodknaux: resultats d'un essai multicentrique contr6l6, randomise, en double insu sur groupes paralleles. Med Chir Dig 1990;19:251-5. 4. Bardhan KD, Long R, Hawkey CJ, Wormsley KG, Brockleberk 0 , Moules I. Lansoprazole, a new protonpump blocker, vs ranitidine in the treatment of reflux erosive esophagitis [Abstract]. Gastroenterology 1991 ; 100:A30. 5. Howden CW. Clinical pharmacology of omeprazole. Clin Pharmacokinet 1991;20:38-49. 6. Delhotal-Landes B, Cournot A, Vermerie N, Dellatolas F, Benoit M, Flouvat B. The effect of food and antacids on lansoprazole absorption and disposition. In: Aiache JM, ed. Proceedings of the Fourth European Congress on Biopharmaceutics and Pharmacokinetics, Geneve; MCdecine et Hygiene. Eur J Drug Metab Pharmacokinet 1991:315-20. 7. Tateno M, Nakamura N. Phase I study of lansoprazole (AG 1749) antiulcer agent. Capsule form. Rinsho Iyaku 1991;7:51-62. 8. Delhotal B, Flouvat B, Cournot A, Duchier J, Dellatolas F. Pharmacocinetique d'un nouvel inhibiteur de la pompe a protons gastrique. Le lansoprazole chez les sujets a risque. In: Bres J , Panis G, eds. Pharmacocinetique: de la recherche la clinique. Proc. 4eme journee
VOLUME 52 NUMBER 5
9. 10. 11.
12.
13.
14.
15.
Mediterranneenne de PharmacocinCtique, Montpellier, 1991. J Pharm Clin Paris, John Libbey Eurotext 1992:242-47. Andersson T. Omeprazole drug interaction studies. Clin Pharmacokinet 1991;21: 195-212. Gugler R, Jensen JC. Omeprazole inhibits oxidative drug metabolism. Gastroenterology 1985;89: 1235-41. Andersson T, Andren K, Cederberg C, Edvardsson G, Heggelund A, Lundborg P. Effect of omeprazole and cimetidine on plasma diazepam levels. Eur J Clin Pharmacol 1990;39:51-4. Andersson T, Cederberg C, Edvardsson G, Heggelund A, Lundborg P. Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. CLINPHARMACOL THER1990; 47:79-85. Vree TB, Baars AM, Hekster YA, Van Der Kleijn E. Simultaneous determination of diazepam and its metabolites N-desmethyldiazepam, oxydiazepam, and oxazepam in plasma and urine of man and dog by means of high-performance liquid chromatography. J Chromatograph 1979;162:605- 14. Zhang Y, Reviriego J , Lou YQ, Sjoqvist F, Bertilsson L. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. CLIN PHARMAC~L THERl990;48:496-502. Delhotal-Landes B, Miscoria G, Flouvat B. Determination of lansoprazole and its metabolites in plasma by high-performance liquid chromatography using a loop column. J Chromatogr 1992;577: 117-22.
Lansoprazole-diazepam nonintevaction 463 16. Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (Multi) for microcomputer. J Pharmacobiodyn 198 1 ;4:879-85. 17. Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet 1978;3:7291. 18. Bertilsson L, Henthorn TK, Sanz E, Tybring G, Sawe J , VillCn T. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. CLINPHARMACOL THER1989:45:348-55. 19. Hanauer G, Graf U, Meissner T. In vivo cytochrome P450 interactions of the newly developed H',KtATPase inhibitor pantoprazole (BY 1023/SK&F96022) compared to other anti-ulcer drugs. Methods Find Exp Clin Pharmacol 1991;13:63-7. 20. Simon WA, Biidingen C, Fahr S, Kinder B, Koske M . The H ' , ~ + - ~ T p a s einhibitor pantoprazole (BY 10231 SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole. Biochem Pharmacol 1991;42:347-55. 21. Kromer W, Postius S, Riedel R, et al. BY 10231 SK&F96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions. J Pharmacol Exp Ther 1990;254:129-35. 22. Somogyi A, Gugler R. Drug interactions with cimetidine. Clin Pharmacokinet 1982;7:23-4 1 .
Romain A. Lefebvre, MD, PhD, Bernard Flouvat, PhD, Sara Karolac-Tamisier, PhD, Emmanuel Moerman, PhD, and Eric Van Ganse, MD Gent and Brussels, Behiurn, and Boulogne, France Lansoprazole is a member of a new class of gastric acid antisecretory drugs, acting by inhibition of the ~ ) the parietal gastric proton pump ( H + , K + - A T P ~ Sin cells.'32 Its effectiveness in the treatment of patients with duodenal ulcers has been established.' A oncedaily dose of 30 or 60 mg is required.3%4Lansoprazole is a substituted benzimidazole. Like the prototype e,~ is drug of this new class, ~ m e ~ r a z o l lansoprazole extensively biotransforrned, mainly by oxidative metabolism. The main metabolites are the sulfone, the sulfide, and hydroxylanzoprazole; the sulfone and the sulfide are also hydroxylated. Urinary elimination, mainly as metabolites, represents only about 25% of ~ - omeprazole, ~ it has been shown that its the d o ~ e . For binding to hepatic cytochrome P450 can inhibit the oxidative metabolism of a limited series of drugs, that is, drugs metabolized by the cytochrome P450 enzyme subfamily IIC.' Diazepam belongs to this group; a re-
From the Heymans Institute of Pharmacology, University of Gent, Gent; the Laboratory of Toxicology and Pharmacokinetics, A. Par6 Hospital, Boulogne-Billancourt; and Roussel Uclaf, Brussels. Received for publication Jan. 28, 1992; accepted June 30, 1992. Supported by Roussel Uclaf, Brussels, Belgium. Reprint requests: Romain A. Lefebvre, MD, PhD, Heymans Institute of Pharmacology, University of Gent, De Pintelaan 185, B-9000 Gent, Belgium. 13/1/40715
duced clearance of diazepam during long-term treatment with omeprazole was shown in three studies, 10-12 The aim of this investigation was to study the possible influence of therapeutic doses of lansoprazole on the pharmacokinetics of a single intravenous dose of diazepam in 12 healthy male volunteers.
METHODS Subjects and study design. White male subjects were judged to be healthy on the basis of past medical histories, physical examinations, electrocardiograms, and laboratory screenings (complete blood cell count with differential, routine blood chemistry, and urinanalyses) 2 weeks before the start of the study. The study was performed in accordance with the Declaration of Helsinki, as revised in Hong Kong, and approved by the Medical Ethics Committee of the University Hospital (Gent, Belgium). Written informed consent was obtained before the study. The study was organized as a placebo-controlled, double-blind randomized crossover study with two treatment periods of 10 days, separated by a washout period of 18 days. Eighteen volunteers were included in the study. Five were excluded because of protocol violations during the washout period. One volunteer stopped the intake of study medication on day 4 of the first treatment period because of diarrhea; "unblinding" at the end of the study revealed that he had been taking placebo. Twelve volunteers (age range, 22 to
VOLUME 52 NUMBER 5
28 years; weight range, 62 to 94 kg; height range, 174 to 201 cm) finished the two treatment periods, and the findings from these subjects were evaluated. Seven of these volunteers started with lansoprazole and five with placebo. Two capsules of 30 mg lansoprazole or placebo were taken once daily before breakfast around 8 A M . On day 7, at the laboratory after they had fasted for at least 8 hours, the subjects took the dose of lansoprazole or placebo with 100 ml water. One hour after intake, diazepam (0.1 mglkg) was administered intravenously to each subject in five fractions (5 seconds per fraction) at 1-minute intervals by way of a cannula in an antecubital vein. The volunteers remained in a semisupine position for 2 hours after the administration of diazepam. Blood was collected in heparinized tubes before the intake of lansoprazole or placebo (lansoprazole blank), before the intravenous injection of diazepam (diazepam blank), and 5 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 24, 3 6 , 4 8 , 6 0 , 72, 84, and 96 hours after the injection of diazepam (start of the injection of the first fraction of diazepam is time 0). Up to 12 hours, two blood samples (5 ml for diazepam and 6 ml for lansoprazole) were obtained by way of a cannula in an antecubital vein in the arm contralateral of the injection site; the samples for lansoprazole were collected in ice-chilled tubes. Samples were centrifuged and the plasma stored at -20" C (diazepam) or -60" C (lansoprazole) until assay. The subjects received standardized meals 2, 6, and 10 hours after the administration of diazepam. The same laboratory screen as performed before the study was done at the end of the study. All other medication was prohibited from 2 days before the start to the end of the study. Two volunteers were light smokers (fewer than five cigarettes a day) and were asked to refrain from smoking during the study. Moderate alcohol intake (maximum, 2 glasses per day) was allowed except for days 7 to 11 of each treatment period. Analytic methods. Plasma concentrations of diazepam and desmethyldiazepam were determined by HPLC with slight modifications from previously described method^.'".'^ Camazepam was used as the internal standard. The chromatographic system consisted of a Waters 510 HPLC pump and a Waters 484 variable wavelength monitor set at 240 nm (Waters Chromatography Div., Millipore, Milford, Mass.) The column was a RoSil C-18HL 5 pm (250 X 4.6 mm, Bio-Rad Laboratories, Eke, Belgium). The chromatograms were recorded on a Waters data and chromatography system with Baseline 8 10 chromatography software (Waters Chromatography Div., Millipore). The mobile phase consisted of 0.1 mollL
Lansoprazole-diazepam noninteraction 459 phosphate buffer (pH 2.7), methanol and acetonitrile (575:30:395), and 100 pl triethanolamineiL. The flow rate was 1.6 mllmin. Plasma samples with high benzodiazepine concentrations were diluted with water at a ratio of 1 :2 or 1 :5 . The detection limit was 5 ngl ml. The between-run accuracy for a plasma pool spiked with 20 and 100 nglml diazepam was 107% and 10 1 %, respectively, with a relative SD of 9.6% and 3.2% ( n = 12). Reference diazepam and desmethyldiazepam were obtained from Roche (Brussels, Belgium); camazepam was obtained from Sintesa (Brussels, Belgium). Plasma lansoprazole was determined as described p r e v i o u ~ l y . The ' ~ detection limit was 3 nglml and the between-run precision for plasma samples spiked with 8, 80, 400, and 2000 nglml was 18.1%, 6.1 %, 5.0%, and 3.8%, respectively (n = 12). Data analysis. The plasma concentration- time profile of diazepam was analyzed with use of the NONLIN computer program ~ u l t i (two-compartmental l~ model); the intravenous administration of diazepam was considered to be a bolus injection. From A, (Y, B, and p , the area under the plasma concentration-time curve to infinity (AUC) was determined. The systemic clearance (CL) was then obtained from DIAUC, in which D is dose. The volume of distribution (V,,,,) during the terminal phase was determined from CLIP, and the half-life of the terminal phase (t,,?) was determined from 0.693lp, in which P is the terminal elimination rate constant. The AUC(0-96) for the metabolite desmethyldiazepam was determined by the trapezoidal method, and its ratio to the AUC(0-96) of diazepam (also determined by the trapezoidal method) was calculated. The AUC of lansoprazole was determined by the trapezoidal method up to the last quantifiable concentration and extrapolated to infinity by use of this last concentration and the apparent elimination rate constant (k,), which was determined by nonlinear regression analysis of the plasma concentrations during the terminal phase. The apparent oral clearance (CLIF), V,,$F, and t,,, were then determined as described for diazepam. Statistical analysis. The findings are given as mean values ? SEM. Statistical analysis was done by means of a two-way ANOVA (subjects and treatments). p Values less than 0.05 were considered to be statistically significant. Standard confidence intervals at 5% were also calculated.
RESULTS All volunteers reported some dizziness, sleepiness, fatigue, or concentration problems during the hours
CLIN PHARMACOL THER NOVEMBER 1992
460 Lefebvre et al.
0
24
48
72
96
72
96
Hours
0
24
48 Hours
Fig. 1. Mean (and SEM) plasma concentrations of diazepam and desmethyldiazepam after single intravenous administration of 0.1 mglkg diazepam, after 7 days of oral treatment with lansoprazole (solid circles) or placebo (open circles).
after the administration of diazepam, except for one volunteer in the placebo session. Two volunteers reported diarrhea under lansoprazole; one reported diarrhea, two reported more frequent defecation and one smoother defecation during placebo administration. The mean plasma diazepam and desmethyldiazepam concentration-time profiles during the lansoprazole and placebo treatment periods are shown in Fig. 1; the pharmacokinetic parameters are given in Table I. No consistent difference in the plasma diazepam concentration-time profile was seen between the lansoprazole and the placebo sessions. The AUC of diazepam during lansoprazole treatment was higher than that
during placebo treatment in eight volunteers but lower in the other four volunteers. The pharmacokinetic parameters of diazepam in the two sessions did not differ significantly. The AUC(0-96) of desmethyldiazepam in the placebo session was 2455.7 '- 161.7 ng - hrlml; the ratio to the AUC(0-96) of diazepam was 0.56 -+ 0.05. In the lansoprazole session, these values were 2379.6 ? 127.0 ng . hrlml and 0.50 2 0.03, respectively, and they were not significantly different from those in the placebo session. The plasma contained a quantifiable amount of lansoprazole up to 9 hours after its administration in eight volunteers, up to 11 hours in three volunteers, and up
VOLUME 52 NUMBER 5
Lansoprazole-diazepam noninteraction 46 1
Fig. 2. Mean (and SEM) plasma concentrations of lansoprazole on the seventh day of oral treatment with 60 mg lansoprazole once daily.
Table I. Pharmacokinetic parameters for single intravenous diazepam (0.1 mglkg) after 1 week of oral placebo or 60 mg lansoprazole AUC (ng . hrlml) Placebo Lansoprazole
Mean SEM Minimum Maximum Confidence interval (%)
4574.1 232.6 3435.4 5775.2
5125.9 317.9 3403.6 7382.0 99- 123
-
CL (mllhrlkg) Placebo Lansoprazole
22.5 1.1 17.3 29.1 -
20.4 1.3 13.5 29.4 81-100
Placebo
Lansoprazole
Placebo
26.0 1.6 18.8 33.8
28.8 2.1 17.3 45.6 98- 123
0.82 0.04 0.68 1.10
-
AUC, Area under the plasma concentration-time curve; CL, total body clearance; tv2, half-life; V,,,,
to 13 hours in one volunteer. The mean plasma lansoprazole concentration- time profile is given in Fig. 2. The maximal plasma concentration of 1453.3 2 151.6 nglml was reached at 1.5 0.1 hour after administration; the apparent plasma elimination tlI2 was 1.0 2 0.04 hour. The CLIF and V,$F were 18.3 2.0 Llhr and 25.5 + 2.3 L, respectively.
*
*
DISCUSSION This study shows that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the kinetics of diazepam. The pharmacokinetic parameters for diazepam during the placebo session were similar to those reported in previous studies. ''-I2 The interindividual variation in the CL of diazepam is large.17 It has been suggested that the metabolism of diazepam in white subjects is related to the mephenytoin hydroxylation phenotype; that is, poor metabolizers of S-mephenytoin show slow diazepam metabo-
v,,,,
t1v2 (hr)
-
@/kg) Lunsopruzole
0.82 0.06 0.66 1.45 91-109
volume of distribution.
lism.I8 The incidence of poor S-mephenytoin metabolism in white subjects is 3% to 5%.14 The plasma tY2of diazepam in our study ranged from 18.8 to 33.8 hours; these figures are clearly below the values (69 to 101 hours) reported in poor metabolizers of S-mephenytoinI8; it therefore seems unlikely that one of the volunteers studied was a slow metabolizer of diazepam. The pharmacokinetics of lansoprazole showed a large intersubject variability, as observed in previous studies. The CLIF, VareaIF, and tlI2 were similar to . ~ those reported previously (Delhotal-Landes et a ~and Flouvat B , Delhotal-Landes B , Cournot A , Dellatolas B. Unpublished data, 1992.) In contrast to what has been observed for omepra~ o l e , ' ~ long-term -'~ treatment with lansoprazole did not influence the metabolism of diazepam. It has been shown that slow metabolizers of omeprazole are also slow metabolizers of diazepam; in this small sub-
462 Lefebwe e t al. group, omeprazole does not interact with diazepam." As described above, our study did not contain slow metabolizers of diazepam, so this is not the explanation for the absence of an interaction. Blood was collected for diazepam and desmethyldiazepam analysis up to 96 hours after administration. This period, corresponding to at least three times the plasma t,,> of diazepam in most cases, should be sufficient to observe an inhibitory influence of lansoprazole on the metabolism of diazepam. In the study of Gugler and ense en," the impairment of diazepam metabolism by omeprazole was clearly observed with a sampling period of only 72 hours after administration. The intake of placebo or lansoprazole was controlled only on the seventh day of the treatment period, when diazepam was also administered; the compliance of the volunteers was further checked by pill count in the drug reservoir on the mornings of days 7 and 11. It seems unlikely that poor compliance can explain the lack of effect of lansoprazole on the metabolism of diazepam because prolongation of the effect of diazepam was observed in rats after single dosing of lans~prazole.'~ In vitro, in rat liver microsomes, lansoprazole was shown to be twice as potent than omeprazole for inhibition of three cytochrome P450 dependent enzymes, that is, dealkylation of 7-ethoxycoumarin, N-demethylation of ethylmorphine, and hydroxylation of lonazolac.20 However, these enzymes belong to the rat cytochrome IIB subfamily, whereas diazepam in humans is metabolized by the cytochrome IIC subfamily.y Still, in rats in vivo it was shown that the effect of diazepam is prolonged after treatment with omeprazole and l a n s o p r a z ~ l e . ' Omeprazole ~~~~ thus inhibits the metabolism of diazepam in both rats and humans, whereas lansoprazole does so only in rats, because our study in humans did not show an interference. This illustrates the difficulties of extrapolating animal data to humans; it should be kept in mind that different species have developed their own specialized cytochrome P450 isozymes. Interaction studies should thus be performed in humans before conclusions on possible clinical advantages of a particular drug can be put forward. Omeprazole and lansoprazole are both substituted benzimidazoles, containing the imidazole ring of cimetidine. This ring structure is thought to be responsible for the inhibitory effect of cimetidine on various drug-metabolizing enzymes in the liver.22 The possible pharmacokinetic interaction with omeprazole was already studied for various drugs, showing that the number of significant interactions with omeprazole is clearly less pronounced than with cimetidine. For ex-
C1.N PHARMACOL THEK NO\'EMRER 1992
ample, for theophylline, warfarin, and phenytoin, which show clinically important interactions with cimetidine, no inhibition or no clinically relevant inhibition of metabolism was observed with ~ m e ~ r a z o l e . ~ The number of enzymes inhibited by omeprazole is thus probably limited. Omeprazole nevertheless clearly impairs the metabolism of diazepam in humans, whereas our study shows that lansoprazole does not. We have no explanation for this difference because both drugs seem to interfere with diazepam metabolism in rats. In view of the wide therapeutic range of diazepam, the degree of inhibition of diazepam metabolism by omeprazole does not seem to be pronounced enough to be clinically r e l e ~ a n t . " ~ ' ~ In conclusion, this study shows that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.
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