Effects of rabeprazole, lansoprazole and omeprazole on intragastric ph in CYP2C19 extensive metabolizers

Transcription

1 Aliment Pharmacol Ther 2002; 16: doi: /j x Effects of rabeprazole, lansoprazole and omeprazole on intragastric ph in CYP2C19 extensive metabolizers T. SAITOH*, Y. FUKUSHIMAà, H. OTSUKA*, J. HIRAKAWA*, H. MORI*, T. ASANOà, T. ISHIKAWAà, T. KATSUBE, K. OGAWA & S. OHKAWA* Departments of *Internal Medicine and Surgery, Tokyo Women s Medical University, Daini Hospital, Tokyo, Japan; àdepartment of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan Accepted for publication 5 July 2002 SUMMARY Aim: To investigate the inhibitory effects on gastric acid secretion of three proton pump inhibitors, omeprazole, lansoprazole and rabeprazole, using a three-way crossover design in healthy Helicobacter pylori-negative, 1 S-mephenytoin 4 -hydroxylase (CYP2C19) homo- and hetero-extensive metabolizers. Methods: Eight healthy Japanese male volunteers were enrolled. After the administration of rabeprazole (10 mg day), lansoprazole (30 mg day) or omeprazole (20 mg day), intragastric ph monitoring was commenced from 24 h before the first proton pump inhibitor dose, and continued for days 1 3 after proton pump inhibitor administration. The ph electrode was used for 48 h and changed just before ph monitoring on day 2. Results: For the administration of 10 mg day rabeprazole, the mean ratios of the 24-h ph 3 holding time were 5.7 ± 1.1%,13.6 ± 2.2%, 35.3 ± 2.7% and 62.8 ± 3.1% for the pre-treatment day and days 1, 2 and 3, respectively. The same ratios for lansoprazole (30 mg day) were 5.7 ± 0.7%, 7.4 ± 1.5%, 13.6 ± 3.4% and 26.6 ± 4.9%; the same ratios for 20 mg day omeprazole were 5.9 ± 0.9%, 6.1 ± 1.2%, 11.4 ± 2.8% and 16.4 ± 4.6%. The mean ratio of the 24-h ph 3 holding time of days 1 3 increased significantly compared to the pre-treatment day (P < 0.01) with the administration of rabeprazole and lansoprazole. The magnitude of inhibition of gastric acid secretion after rabeprazole administration was stronger than that after lansoprazole. A significant elevation of the mean ratio of the 24-h ph 3 holding time was demonstrated on days 2 and 3 with omeprazole (P < 0.01). Conclusions: In H. pylori-negative CYP2C19 extensive metabolizers, rabeprazole (10 mg day) shows a faster onset of rising intragastric ph and a stronger inhibition of gastric acid secretion than do lansoprazole (30 mg day) or omeprazole (20 mg day). INTRODUCTION Proton pump inhibitors, such as omeprazole, lansoprazole and rabeprazole, have been widely used for the treatment of acid-related disease. Comparative studies Correspondence to: Dr T. Saitoh, Department of Internal Medicine, Tokyo Women s Medical University, Daini Hospital, Nishiogu, Arakawa-ku, Tokyo , Japan. ssumiko@fa2.so-net.ne.jp have demonstrated that proton pump inhibitors provide acid secretion, pain relief and ulcer healing superior to those achieved with histamine H 2 -receptor antagonists. 1 Although many studies have shown that multiple administration (usually more than 7 days) of proton pump inhibitors provides a sufficient intragastric ph for the relief of pain, ulcer healing and the eradication of Helicobacter pylori, 2 5 few reports have discussed the changes in gastric ph monitored in the early post-administration phase or the patterns of Ó 2002 Blackwell Science Ltd 1811

2 1812 T. SAITOH et al. changes in the gastric ph analysed before the occurrence of the maximal inhibition of gastric acid secretion. Although changes in gastric ph in the early postadministration phase have been examined, the timing of the elevation of gastric ph and the patterns of changes in the ph have varied widely between studies. In the daily clinical setting, a faster onset of rising intragastric ph and a stronger inhibition of gastric acid secretion of proton pump inhibitors may be crucial for symptomatic relief in patients with peptic ulcers and gastro-oesophageal reflux disease. There are some differences between proton pump inhibitors with regard to their potency and the time from the onset of the inhibition of acid secretion until they show a clinical effect. This is due to differences in the rate of acid-induced chemical activation of proton 2 pump inhibitors to their respective cyclic sulphenamide or metabolic pathways as a result of differences in 3 molecular structure. 6, 7 Recently, subject-related factors, such as H. pylori infection and S-mephenytoin 44 -hydroxylase (CYP2C19) genotype, have been reported to influence the inhibitory action of proton pump inhibitors on gastric acid secretion in the early postadministration phase It has been reported that the inhibitory action of omeprazole on gastric acid secretion decreases after successful eradication therapy in H. pylori-positive subjects This indicates that H. pylori infection of the gastric mucosa potentiates the effects of proton pump inhibitors. Proton pump inhibitors are inactivated by metabolism in the liver, especially by CYP2C19 and CYP3A4 of cytochrome P450 (CYP), and differences in the metabolic profiles between proton pump inhibitors and in the metabolic capacities of subjects could have a profound influence on drug efficacy. Indeed, large differences in plasma drug levels have been shown between CYP2C19 extensive metabolizers and poor metabolizers, and these also influence the degree of inhibition of acid secretion. Furuta et al. reported that, when the gastric ph was measured following the oral administration of omeprazole to H. pylori-negative subjects, significantly lower mean gastric ph levels were observed in extensive metabolizers than in poor metabolizers. 14 Although rabeprazole is also a substituted benzimidazole sulphoxide, the drug has a different metabolic profile compared to that of the other proton pump inhibitors. Rabeprazole is metabolized mainly via a non-enzymatic reduction to the thioether rabeprazole, and CYP2C19 and CYP3A4 are only partly involved in the metabolism of rabeprazole. 9 Therefore, the acid inhibitory effect of rabeprazole is supposed to be less influenced by the CYP2C19 phenotype or genotype status compared to that of other proton pump inhibitors, such as lansoprazole or omeprazole. Recently, Shirai et al. have studied the influence of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric ph, and have concluded that the acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes. 7 Rabeprazole shows a greater and faster acid inhibitory effect than omeprazole; 2, 7 however, there are few data available on the comparison of the acid inhibitory effects of rabeprazole and lansoprazole. 6 We believe that CYP2C19 extensive metabolizers would be more suitable for the differentiation and evaluation of the acid inhibitory effects of proton pump inhibitors. Therefore, we investigated the effects of rabeprazole, lansoprazole and omeprazole on intragastric ph in CYP2C19 extensive metabolizers in the early phase of the post-administration period by continuous monitoring of the gastric ph from 24 h prior to the administration of the proton pump inhibitor to the third day after administration. SUBJECTS AND METHODS Subjects The subjects were eight healthy male volunteers, aged between 24 and 48 years and weighing kg. All volunteers gave written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. The subjects were all negative for anti- H. pylori immunoglobulin G antibodies (SRL Inc, Tokyo, Japan), confirmed by the 13 C-urea breath test (Ubit- IR200, Ohtsuka Electronics, Tokyo, Japan). CYP2C19 genotyping DNA samples were obtained from the eight individuals. The samples were analysed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to detect the CYP2C19 genotype according to a previously reported technique. 15 It has been reported that there are two point mutations in the CYP2C19 gene. The wild-type allele has G at position

3 INTRAGASTRIC ph AFTER PPI ADMINISTRATION in exon 4 and G at position 689 in exon 5 of CYP2C19. One (m1 allele) of the mutated alleles has A at position 689 in exon 5. Another mutated allele (m2 16, 17 allele) has A at position 636 in exon 4. Four individuals were genotyped as homozygous extensive metabolizers (homo-extensive metabolizers) who had two wild-type alleles. Another four individuals were genotyped as heterozygous extensive metabolizers (hetero-extensive metabolizers) who had one wild-type allele and one m1 allele (SRL Inc, Tokyo, Japan). Study protocol The first 24 h of intragastric ph monitoring in all subjects represented the pre-treatment period. Rabeprazole (10 mg) (Pariet, Eisai Co. Ltd, Tokyo, Japan), lansoprazole (30 mg) (Takepron, Takeda Co. Ltd, Osaka, Japan) or omeprazole (20 mg) (Omepral, Fujisawa Pharmaceutical Co. Ltd, Osaka, Japan) was administered the following day 30 min after the evening meal, and the same agent was administered on days 2 and 3 at around the same time. The order of administration of the test agents for each subject was randomized in a crossover manner. The washout periods between studies were at least 2 weeks, and so each subject completed the study on all three test drugs within a 4-month period. Subjects were instructed to take three meals a day: dinner at h, breakfast at h and lunch at h. Meals were not standardized, but subjects were asked to keep the contents of each meal as similar as possible. 48-h ph-metry The ph electrode was inserted transnasally under local anaesthesia and positioned fluoroscopically, so that the electrode was located in the body of the stomach, 5 cm distal to the cardia. Monitoring was performed continuously for 48 h from h, after which time the ph electrode was changed over within 40 min, and monitoring was continued for a further 48 h. The gastric ph was measured at 10-s intervals by a portable ph meter attached to the glass ph electrode (Chemical Instrument Co. Ltd, Tokyo, Japan). The ph electrode was calibrated before each recording using standard buffer solutions of ph 1.68 and ph At the end of each recording, the data were transferred to a personal computer and stored until analysed with the software (Chemical Instrument Co. Ltd, Tokyo, Japan). The 24-h monitoring period was divided into daytime ( h) and night-time ( h) periods. Table 1. Intragastric ph 3 holding time (%) after the administration of proton pump inhibitors for 3 days Treatment (dose day) Study period (time) ph 3 holding time (%) Baseline Day 1 Day 2 Day 3 Rabeprazole 24 h 5.74 ± } 2.22* } 2.67* ± 3.12* (10 mg day) ( h) ( ) ( ) ( ) ( ) Night-time; 8 h ± 3.27* ± 5.97* ( h) ( ) ( ) Daytime; 16 h ± ± 4.45* ± 3.99* ± 3.50* ( h) ( ) ( ) ( ) ( ) Lansoprazole 24 h 5.66 ± ± 1.49* ± 3.42* ± 4.87* (30 mg day) ( h) ( ) ( ) ( ) ( ) Night-time; 8 h ± 4.93* ( h) ( ) Daytime; 16 h ± ± 3.35* ± 7.77* ± 8.69* ( h) ( ) ( ) ( ) ( ) Omeprazole 24 h 5.86 ± ± ± 2.79* ± 4.55* (20 mg day) ( h) ( ) ( ) ( ) ( ) Night-time; 8 h ( h) Daytime; 16 h ± ± ± 5.18* ± 8.67* ( h) ( ) ( ) ( ) ( ) Mean ± s.d. (range). * P < 0.01 vs. baseline data.

4 1814 T. SAITOH et al. Statistical analysis A 24-h profile of intragastric ph was obtained for each subject at baseline and on days 1 3 of dosing. The mean percentage of time for which the intragastric ph > 3 (ph 3 holding time) was calculated for each subject during each dosing session and suitable intervals (daytime, h; night-time, h). All numerical data listed in Table 1 are given as the mean ± s.d and (range). Differences in the ph 3 holding time for each day after drug administration were compared with the baseline data using the paired t-test with the Bonferroni method to correct for multiplicity. A P value of less than ( ¼ ) was considered to be statistically significant. Statistical calculations were performed using a SAS software system. RESULTS The mean 24-h intragastric ph profiles for the pretreatment period and days 1, 2 and 3 of the postadministration phase for rabeprazole (10 mg) (top), lansoprazole (30 mg) (middle) and omeprazole (20 mg) (bottom) are shown in Figure 1. The mean percentage of time for which the intragastric ph > 3 (ph 3 holding time, %) after the administration of the three proton pump inhibitors for 3 days is summarized in Table 1. The mean ratios of the 24-h, daytime period and night-time period ph 3 holding time for the pretreatment period and days 1 3 after administration, for each proton pump inhibitor, are shown in Figure 1. The baseline data for the 24-h intragastric ph time curves (Figure 1) and ph 3 holding time (%, Table 1) were fairly similar for the three proton pump inhibitors. After the administration of 10 mg rabeprazole, the mean 24-h intragastric ph time curves showed an elevation by a value of unity overall, and a prolongation of the post-prandial ph elevation in comparison with the baseline data on day 2. On day 3, there was a further prolonged period of ph 3 from the middle of the night to the early morning hours. The mean ratio of the 24-h ph 3 holding time was 5.7 ± 1.1% for the pre-treatment period, which increased to 13.6 ± 2.2%, 35.3 ± 2.7% and 62.8 ± 3.1% for days 1, 2 and 3, respectively. The mean ratio of the ph 3 holding time for days 1 3 increased significantly compared with the baseline data for the 24-h and daytime periods (P < 0.01, Figure 2 and Table 1). Figure 1. Mean 24-h intragastric ph profiles after the administration of 10 mg rabeprazole (top; RPZ), 30 mg lansoprazole (middle; LPZ) and 20 mg omeprazole (bottom; OPZ) for the pretreatment period and on days 1, 2 and 3 after administration in the eight CYP2C19 extensive metabolizers. The thin line represents baseline recordings, the thick line indicates day 1, the dotted line indicates day 2 and the broken line indicates day 3. In the case of 30 mg lansoprazole, the mean 24-h intragastric ph profiles showed a definite increase on days 2 and 3 compared with the pre-treatment period. The mean ratios of the 24-h ph 3 holding time were 5.7 ± 0.7%, 7.4 ± 1.5%, 13.6 ± 3.4% and 26.6 ± 4.9% for the pre-treatment period and days 1, 2 and 3, respectively. A significant increase in the mean ratio of the ph 3 holding time was observed on days 1 3 (P < 0.01, Figure 2 and Table 1). However, the

5 INTRAGASTRIC ph AFTER PPI ADMINISTRATION 1815 Figure 2. The mean ratio of the 24-h, daytime period ( h) and night-time period ( h) ph 3 holding time (%) for the pre-treatment period and days 1, 2 and 3 after administration with each proton pump inhibitor. The filled circle, filled triangle and filled square represent the mean ratio of the ph 3 holding time with 10 mg rabeprazole, 30 mg lansoprazole and 20 mg omeprazole, respectively. Mean ± s.d. *P < 0.01 vs. baseline data. magnitude of the inhibition of gastric acid secretion after rabeprazole administration was stronger than that after lansoprazole administration. With the administration of 20 mg omeprazole, the mean 24-h intragastric ph time curves were similar on days 1 3. A slight increase in the inhibition of gastric acid secretion was found only on day 3. The mean ratios of the 24-h ph 3 holding time were 5.9 ± 0.9%, 6.1 ± 1.2%, 11.4 ± 2.8% and 16.4 ± 4.6% for the pretreatment period and days 1, 2 and 3, respectively. A significant elevation of the mean ratio of the ph 3 holding time was demonstrated on days 2 and 3 with omeprazole (P < 0.01, Figure 2 and Table 1). DISCUSSION In this study, we examined the changes in intragastric ph after the administration of rabeprazole, lansoprazole and omeprazole in the early post-administration phase (days 1 3 of treatment) in H. pylori-negative CYP2C19 extensive metabolizers. We observed that, during the early post-administration phase, rabeprazole showed a faster onset and stronger inhibition of intragastric acid secretion than omeprazole and lansoprazole. A significant increase in intragastric ph 3 over 24 h and during the daytime period ( h) was observed from day 1 with rabeprazole, but not with omeprazole. Lansoprazole also showed a significant increase in intragastric ph 3 over 24 h and during the daytime period; however, the magnitude was smaller than that with rabeprazole. This study supports the reports by Williams et al. 2 and Shirai et al. 7 that the initial dose of rabeprazole (20 mg) has a significantly faster onset of inhibition of intragastric acid secretion than that of omeprazole (20 mg). The present results are also supported by the faster and stronger activation of rabeprazole observed in an in vitro study. This was a study of the half-maximum inhibitory concentration (IC 50 ) of rabeprazole and omeprazole for H +,K + -ATPase in hog gastric vesicles measured using the pyruvate kinase lactate dehydrogenase linked system. Based on this study, the IC 50 values of rabeprazole and omeprazole were 0.07 lm and 0.47 lm, respectively. This result indicates that the inhibitory activity of rabeprazole was 6.5 times higher than that of omeprazole. 18 In addition, in an in vitro study of H +, K + - ATPase inhibitory activity using hog gastric vesicles, rabeprazole showed the complete inhibition of H +,

6 1816 T. SAITOH et al. K + -ATPase within 5 min, 19 whereas lansoprazole and omeprazole inhibited the enzyme activity after 5 min. 18, 19 These results suggest that the acid-induced 6activation rate and intensity of sulphenamide depend on their chemical structure, and that rabeprazole is the fastest and strongest proton pump inhibitor to be activated in the acid environment at ph Lansoprazole (30 mg) and omeprazole (20 mg) showed a 30 60% inhibitory effect on pentagastrinstimulated acid secretion on days 1 and 2 after drug administration, 20 suggesting that rabeprazole may have the potential to inhibit H +, K + -ATPase in a similar manner to lansoprazole and omeprazole. Based on the investigations to date on omeprazole in the early postadministration phase, it is generally understood that the first administered dose inhibits only H +, K + -ATPase present in the canalicular membrane, the actual inhibitory effects on gastric acid secretion develop only after the third dose, and 66% of the maximum acid secretion is inhibited on day 5 after drug administration, depending on the degree of activation of H +,K + - ATPase in the resting phase in wall cells and on the recovery of disulphide bonds between the inhibitors and H +, K + -ATPase. 21 It has also been reported that an inhibitory effect of 20 40% on pentagastrin-stimulated acid secretion developed on day 2 for 20 mg omeprazole administration, and 52% on day 1 and 63% on day 2 for 30 mg lansoprazole, compared with placebo, and that the inhibitory action on H +,K + -ATPase that was activated by pentagastrin stimulation appeared as early as day 1 for 30 mg lansoprazole and on day 2 for 20 mg omeprazole. 20 We found a small increase in the gastric ph at midnight for several hours after the first dose of rabeprazole and the prolongation of higher ph values on days 2 and 3, suggesting a different potency of inhibition of acid secretion for rabeprazole compared with that for lansoprazole and omeprazole. It could be speculated that rabeprazole, with its higher pk a value, inhibits acid secretion more rapidly and more strongly than omeprazole and lansoprazole by inhibiting not only the active H +, K + -ATPase present in canalicular membranes, but also the resting H +,K + -ATPase in the cells. Finally, it is proposed that the faster rates of rabeprazole with regard to both the formation of active intermediates and the inhibition of the total H +, K + - ATPase in parietal cells, compared with lansoprazole and omeprazole, could be responsible for the rapid rise in the gastric ph levels in the early post-administration phase. As the administration of 10 mg rabeprazole shows a faster onset and stronger inhibition of intragastric ph in H. pylori-negative CYP2C19 extensive metabolizers than that obtained with 30 mg lansoprazole or 20 mg omeprazole, rabeprazole may be useful for the faster resolution of symptoms in the treatment of acid-related diseases. ACKNOWLEDGEMENTS This research was supported in part by a grant (to T. Saitoh, no ) from the Ministry of Education, Science and Culture, Japan. REFERENCES 1 Sachs G. Proton pump inhibitors and acid-related diseases. Pharmacotherapy 1997; 17: Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998; 12: Bruley Des Varannes S, Levy P, Lartigue S, et al. Comparison of lansoprazole with omeprazole on 24-hour intragastric ph, acid secretion and serum gastrin in healthy volunteers. Aliment Pharmacol Ther 1994; 8: Hartmann M, Theiss U, Huber R, et al. Twenty-four-hour intragastric ph profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole. Aliment Pharmacol Ther 1996; 10: Geus WP, Mulder PG, Nicolai JJ, et al. Acid-inhibitory effects of omeprazole and lansoprazole in Helicobacter pylori-negative healthy subjects. Aliment Pharmacol Ther 1998; 12: Adachi K, Katsube A, Kawamura T, et al. CYP2C19 genotype status and intragastric ph during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther 2000; 14: Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric ph. Aliment Pharmacol Ther 2001; 15: Klotz U. Pharmacokinetic considerations in the eradication of Helicobacter pylori. Clin Pharmacokinet 2000; 38: Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors emphasis on rabeprazole. Aliment Pharmacol Ther 1999; 13(Suppl. 3): Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996; 31: Verdu EF, Armstrong D, Idstrom J-P, et al. Effect of curing Helicobacter pylori status on intragastric ph during treatment with omeprazole. Gut 1995; 37:

7 INTRAGASTRIC ph AFTER PPI ADMINISTRATION Labenz J, Tilleburg B, Peitz U, et al. Helicobacter pylori augments the ph-increasing effect of omeprazole in patients with duodenal ulcer. Gastroenterology 1996; 110: Martinek J, Blum A, Stote M, et al. Effects of pumazole (BY841), a novel reversible proton pump antagonist, and of omeprazole, on intragastric acidity before and after cure of Helicobacter pylori infection. Aliment Pharmacol Ther 1999; 13: Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric ph in humans. Clin Pharmacol Ther 1999; 65: Kubota T, Chiba K, Ishizaki T. Genotyping of S-mephenytoin 4 -hydroxylation in an extended Japanese population. Clin Pharmacol Ther 1996; 60: de Morais SMF, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: de Morais SMF, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol Pharmacol 1994; 46: Morii M, Takata H, Fujisaki H, et al. The potency of substituted benzimidazoles such as E-3810, omeprazole, Ro to inhibit gastric H +,K + -ATPase is correlated with the rate of acid-activation of the inhibitor. Biochem Pharmacol 1990; 39: Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of the gastric H +,K + -ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997; 272: Muller P, Goksu A, Fuchs F, et al. Initial potency of lansoprazole and omeprazole tablets on pentagastrin-stimulated gastric acid secretion: a placebo-controlled study in healthy volunteers. Aliment Pharmacol Ther 2000; 14: Modlin IM, Sachs G. Inhibition of the gastric acid pump. In: Modlin IM, Sachs G, eds. Acid Related Diseases. Milan: 8 Schnetztor-Verlag Gmbh D-Konstanz, 1998: