Influence of the Meal and Genotype of CYP2C19 on the Pharmacokinetics of Proton Pump Inhibitors in Healthy Japanese Subjects

Hirohiko Shinkai, Tomoyuki Koike, Miki Shimada, Kenichiro Nakagawa, Katsunori Iijima, Yotaro Matsumoto, Masamitsu Maekawa, Nariyasu Mano, Tooru Shimosegawa

Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan..
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;.

DOI: 10.4236/pp.2013.46073                

Abstract

Objectives: To evaluate the influence of meals on the pharmacokinetics of omeprazole and rabeprazole and to investigate these PPIs with reference to CYP2C19 genotypes in healthy Japanese men. Methods: This was a randomized, open label, four-way crossover study. Twelve healthy Japanese male volunteers received a single oral dose of either 20 mg omeprazole or 10 mg rabeprazole, in the fasted state and after a standardized breakfast. Results: Between the administration of omeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC, Tmax, and half-life. Between the administration of rabeprazole in the fasted state and after breakfast, there were no significant differences in Cmax, AUC and half-life, whereas the Tmax of rabeprazole after breakfast was significantly delayed (2.8 ± 1.0 vs 5.3 ± 1.8 h, respectively; p = 0.006). PMs demonstrated the highest Cmax and AUC after drug intake under the fasting state and after breakfast, and homo EMs showed a significantly delayed Tmax. Conclusion: When a single dose of either PPI was administered, the pharmacokinetics of omeprazole was not affected by the meal, whereas the Tmax of rabeprazole after the meal was significantly delayed.

Keywords

Proton Pump Inhibitor; Omeprazole; Rabeprazole; CYP2C19; Pharmacokinetics

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	G. R. Locke 3rd, N. J. Talley, S. L. Fett, A. R. Zinsmeister and L. J. Melton 3rd, “Prevalence and Clinical Spectrum of Gastroesophageal Reflux: A Population-Based Study in Olmsted County, Minnesota,” Gastroenterology, Vol. 112, 1997, pp. 1448-1456. doi:10.1016/S0016-5085(97)70025-8
[2]	M. Diaz-Rubio, C. Moreno-Elola-Olaso, E. Rey, G. R. Locke 3rd and F. Rodriguez-Artalejo, “Symptoms of Gastro-Oesophageal Reflux: Prevalence, Severity, Duration and Associated Factors in a Spanish Population,” Alimentary Pharmacology & Therapeutics, Vol. 19, No. 1, 2004, pp. 95-105. doi:10.1046/j.1365-2036.2003.01769.x
[3]	V. Stanghellini, “Three-Month Prevalence Rates of Gastrointestinal Symptoms and the Influence of Demographic Factors: Results from the Domestic/International Gastroenterology Surveillance Study (DIGEST),” Scandinavian Journal of Gastroenterology, Vol. 34, No. 231, 1999, pp. 20-28. doi:10.1080/003655299750025237
[4]	Y. Fujiwara, K. Higuchi, Y. Watanabe, M. Shiba, T. Watanabe, K. Tominaga, N. Oshitani, T. Matsumoto, H. Nishikawa and T. Arakawa, “Prevalence of Gastroesophageal Reflux Disease and Gastroesophageal Reflux Disease Symptoms in Japan,” Journal of Gastroenterology and Hepatology, Vol. 20, No. 1, 2005, pp. 26-29. doi:10.1111/j.1440-1746.2004.03521.x
[5]	K. Fujimoto, R. Iwakiri, K. Okamoto, K. Oda, A. Tanaka, S. Tsunada, H. Sakata, A. Kikkawa, R. Shimoda, K. Matsunaga, K. Watanabe, B. Wu, S. Nakahara, H. Ootani and A. Ootani, “Characteristics of Gastroesophageal Reflux Disease in Japan: Increased Prevalence in Elderly Women,” Journal of Gastroenterology, Vol. 38, Suppl. 15, 2003, pp. 3-6.
[6]	S. Ohara, T. Kouzu, T. Kawano and M. Kusano, “Nationwide Epidemiological Survey Regarding Heartburn and Reflux Esophagitis in Japanese,” Nippon Shokakibyo Gakkai Zasshi, Vol. 102, No. 8, 2005, pp. 1010-1024.
[7]	M. Inamori, J. Togawa, H. Nagase, Y. Abe, T. Umezawa, A. Nakajima, T. Saito, N. Ueno, K. Tanaka, H. Sekihara, H. Kaifu, H. Tsuboi, H. Kayama, S. Tominaga and H. Nagura, “Clinical Characteristics of Japanese Reflux Esophagitis Patients as Determined by Los Angeles Classification,” Journal of Gastroenterology and Hepatology, Vol. 18, No. 2, 2003, pp. 172-176. doi:10.1046/j.1440-1746.2003.02932.x
[8]	N. J. Bell, D. Burget, C. W. Howden, J. Wilkinson and R. H. Hunt, “Appropriate Acid Suppression for the Management of Gastrooesophageal Reflux Disease,” Digestion, Vol. 51, Suppl. 1, 1992, pp. 59-67. doi:10.1159/000200917
[9]	E. Fellenius, T. Berglindh, G. Sachs, et al., “Substituted Benzimidazoles Inhibit Gastric Acid Secretion by Blocking (H++ K+) ATPase,” Nature, Vol. 290, 1981, pp. 159-161. doi:10.1038/290159a0
[10]	G. Sachs, J. M. Shin, C. Briving, et al., “The Pharmacology of the Gastric Acid Pump: The H+, K+ ATPase,” Annual Review of Pharmacology and Toxicology, Vol. 35, 1995, pp. 277-305. doi:10.1146/annurev.pa.35.040195.001425
[11]	T. Andersson, C. G. Regardh, Y. C. Lou, et al., “Polymorphic Hydroxylation of S-Mephenytoin and Omeprazole Metabolism in Caucasian and Chinese Subjects,” Pharmacogenetics, Vol. 2, 1992, pp. 25-31. doi:10.1097/00008571-199202000-00005
[12]	M. Chang, G. Tybring, M. L. Dahl, et al., “Interphenotype Differences in Disposition and Effect on Gastrin Levels of Omeprazole—Suitability of Omeprazole as a Probe for CYP2C19,” British Journal of Clinical Pharmacology, Vol. 39, No. 5, 1995, pp. 511-518. doi:10.1111/j.1365-2125.1995.tb04488.x
[13]	T. Furuta, K. Ohashi, K. Kosuge, et al., “CYP2C19 Genotype Status and Effect of Omeprazole on Intragastric pH in Humans,” Clinical Pharmacology & Therapeutics, Vol. 65, No. 5, 1999, pp. 552-561. doi:10.1016/S0009-9236(99)70075-5
[14]	T. Andersson, J. O. Miners, M. E. Veronese, et al., “Identification of Human Liver Cytochrome P450 Isoforms Mediating Secondary Omeprazole Metabolism,” British Journal of Clinical Pharmacology, Vol. 37, No. 6, 1994, pp. 597-604. doi:10.1111/j.1365-2125.1994.tb04310.x
[15]	L. Pichard, G. Gillet, C. Bonfils, et al., “Oxidative Metabolism of Zolpidem by Human Liver Cytochrome P450S,” Drug Metabolism and Disposition, Vol. 23, No. 11, 1995, pp. 1253-1262.
[16]	K. Adachi, T. Katsube, A. Kawamura, et al., “CYP2C19 Genotype Status and Intragastric pH during Dosing with Lansoprazole or Rabeprazole,” Alimentary Pharmacology & Therapeutics, Vol. 14, No. 10, 2000, pp. 1259-1266. doi:10.1046/j.1365-2036.2000.00840.x
[17]	Y. Horai, M. Kimura, H. Furuie, K. Matsuguma, S. Irie, Y. Koga, T. Nagahama, M. Murakami, T. Matsui, T. Yao, A. Urae and T. Ishizaki, “Pharmacodynamic Effects and Kinetic Disposition of Rabeprazole in Relation to CYP2C19 Genotypes,” Alimentary Pharmacology & Therapeutics, Vol. 15, No. 6, 2001, pp. 793-803. doi:10.1046/j.1365-2036.2001.00980.x
[18]	N. Shirai, T. Furuta, Y. Moriyama, H. Okochi, K. Kobayashi, M. Takashima, F. Xiao, K. Kosuge, K. Nakagawa, H. Hanai, K. Chiba, K. Ohashi and T. Ishizaki, “Effects of CYP2C19 Genotypic Differences in the Metabolism of Omeprazole and Rabeprazole on Intragastric pH,” Alimentary Pharmacology & Therapeutics, Vol. 15, No. 12, 2001, pp. 1929-1937. doi:10.1046/j.1365-2036.2001.01108.x
[19]	T. Saitoh, Y. Fukushima, H. Otsuka, J. Hirakawa, H. Mori, T. Asano, T. Ishikawa, T. Katsube, K. Ogawa and S. Ohkawa, “Effects of Rabeprazole, Lansoprazole and Omeprazole on Intragastric pH in CYP2C19 Extensive Metabolizers,” Alimentary Pharmacology & Therapeutics, Vol. 16, No. 10, 2002, pp. 1811-1817. doi:10.1046/j.1365-2036.2002.01348.x
[20]	T. Shimatani, M. Inoue, T. Kuroiwa, J. Xu, H. Mieno, M. Nakamura and S. Tazuma, “Acid-Suppressive Effects of Rabeprazole, Omeprazole, and Lansoprazole at Reduced and Standard Doses: A Crossover Comparative Study in Homozygous Extensive Metabolizers of Cytochrome P450 2C19,” Clinical Pharmacology & Therapeutics, Vol. 79, No. 1, 2006, pp. 144-152. doi:10.1016/j.clpt.2005.09.012
[21]	M. Kanemaru, M. Nakashima, T. Kajiho, Y. Matsuda and T. Oka, “Inhibition of Gastric Secretion by Omeprazole, a Proton Pump Inhibitor-Effect on Basal and Tetragastrin-Stimulated Gastric Secretions in Healthy Volunteers,” Rinsyoiyaku, Vol. 5, No. 1, 1989, pp. 13-28.
[22]	T. Lind, C. Cederberg, G. Ekenved, U. Haglund and L. Olbe, “Effect of Omeprazole—A Gastric Proton Pump Inhibitor—On Pentagastrin Stimulated Acid Secretion in Man,” Gut, Vol. 24, No. 4, 1983, pp. 270-276. doi:10.1136/gut.24.4.270
[23]	M. Nakashima, M. Kanemaru, H. Hashimoto, Y. Takiguchi, A. Mizuno, T. Kajiho, T. Oka and Y. Matsuda, “Phase I Study of Omeprazole-Single-Dose and Multiple-Dose Studies,” Japanese Journal of Clinical Pharmacology and Therapeutics, Vol. 19, No. 4, 1988, pp. 667-679.
[24]	S. Yasuda, A. Ohnisi, T. Ogawa, Y. Tomono, J. Hasegawa, H. Nakai, Y. Shimamura and N. Morishita, “Pharmacokinetic Properties of E3810, a New Proton Pump Inhibitor, in Healthy Male Volunteers,” International Journal of Clinical Pharmacology and Therapeutics, Vol. 32, No. 9, 1994, pp. 466-473.
[25]	M. Bannai, K. Higuchi, T. Akesaka, et al., “Single-Nucleotide-Polymorphism Genotyping for Whole-Genome-Amplified Samples Using Automated Fluorescence Correlation Spectroscopy,” Analytical Biochemistry, Vol. 327, No. 2, 2004, pp. 215-221.
[26]	C. H. Oliveira, R. E. Barrientos-Astigarraga, E. Abib, G. D. Mendes, D. R. da Silva and G. de Nucci, “Lansoprazole Quantification in Human Plasma by Liquid Chromatography-Electrospray Tandem Mass Spectrometry,” Journal of Chromatography B, Vol. 783, No. 2, 2003, pp. 453-459. doi:10.1016/S1570-0232(02)00711-0
[27]	J. Huang, Y. Xu, S. Gao, L. Rui and Q. Guo, “Development of a Liquid Chromatography/Tandem Mass Spectrometry Assay for the Quantification of Rabeprazole in Human Plasma,” Rapid Communications in Mass Spectrometry, Vol. 19, No. 16, 2005, pp. 2321-2324. doi:10.1002/rcm.2066
[28]	L. Z. Benet, D. L. Kroetz and L. B. Sheiner, “Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination,” In: J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon and A. G. Gilman, Eds., Goodman and Gilman’s: The Pharmacolgical Basis of Therapeutics, 9th Edition, Mcgraw-Hill, New York, 1996, pp. 3-28.
[29]	E. A. Mayer, “The Physiology of Gastric Storage and Emptying,” In: L. R. Johnson, D. H. Alpers, E. D. Jacobson, J. Christensen and J. H. Walsh, Eds., Physiology of the Gastrointestinal, 3rd Edition, Raven Press, New York, 1994, pp. 929-976.
[30]	K. Ewe, A. G. Press, S. Bollen and I. Schuhn, “Gastric Emptying of Indigestible Tablets in Relation to Composition and Time of Ingestion of Meals Studied by Metal Detector,” Digestive Diseases and Sciences, Vol. 36, No. 2, 1991, pp. 146-152. doi:10.1007/BF01300748
[31]	C. Larson, N. J. Cavuto, D. A. Flockhart and R. B. Weinberg, “Bioavailability and Efficacy of Omeprazole Given Orally and by Nasogastric Tube,” Digestive Diseases and Sciences, Vol. 41, No. 3, 1996, pp. 475-479.
[32]	T. Furuta, N. Shirai, M. Sugimoto, A. Nakamura, A. Hishida and T. Ishizaki, “Influence of CYP2C19 Pharmacogenetic Polymorphism on Proton Pump Inhibitor-Based Therapies,” Drug Metabolism and Pharmacokinetics, Vol. 20, No. 3, 2005, pp. 153-167. doi:10.2133/dmpk.20.153
[33]	S. Yasuda, A. Ohnishi, T. Ogawa, Y. Tomono, et al., “Pharmacokinetic Properties of E3810, a New Proton Pump Inhibitor in Healthy Male Volunteers,” International Journal of Clinical Pharmacology and Therapeutics, Vol. 32, No. 9, 1994, pp. 466-473.
[34]	X. Q. Li, T. B. Andersson, M. Ahlstrom and L. Weidolf, “Comparison of Inhibitory Effects of the Proton Pump Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metabolism and Disposition, Vol. 32, No. 8, 2004, pp. 821-827. doi:10.1124/dmd.32.8.821
[35]	H. G. Xie, C. M. Stein, R. B. Kim, G. R. Wilkinson, D. A. Flockhart and A. J. Wood, “Allelic, Genotypic and Phenotypic Distributions of S-Mephenytoin 4’-Hydroxylase (CYP2C19) in Healthy Caucasian Populations of European Descent Throughout the World,” Pharmacogenetics, Vol. 9, No. 5, 1999, pp. 539-549. doi:10.1097/00008571-199910000-00001
[36]	M. P. Williams, J. Sercombe, M. I. Hamilton and R. E. Pounder, “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,” Alimentary Pharmacology & Therapeutics, Vol. 12, No. 11, 1998, pp. 1079-1089. doi:10.1046/j.1365-2036.1998.00418.x