Influence of CYP2C19 Pharmacogenetic Polymorphism on Proton Pump Inhibitor-based Therapies

doi:10.2133/dmpk.20.153

Drug Metabolism and Pharmacokinetics

Volume 20, Issue 3, 2005, Pages 153-167

https://doi.org/10.2133/dmpk.20.153 Get rights and content

Summary:

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are mainly metabolized by CYP2C19 in the liver. There are genetically determined differences in the activity of this enzyme. The genotypes of CYP2C19 are classified into the three groups, rapid extensive metabolizer (RM), intermediate metabolizer (IM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs depend on CYP2C19 genotype status. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs influence the cure rates for the gastro-esophageal reflux disease and H. pylori infection by PPI-based therapies. For the better PPI-based treatment, doses and dosing schemes of PPIs should be optimized based on CYP2C19 genotype status.

References (95)

N. Inatomi et al.
Effects of a proton pump inhibitor, AG-1749 (lansoprazole), on reflux esophagitis and experimental ulcers in rats
Jpn. J. Pharmacol.
(1991)
S.M. de Morais et al.
The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans
J. Biol. Chem.
(1994)
P.L. Peghini et al.
Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors
Am. J. Gastroenterol.
(1998)
T.M. Ours et al.
Nocturnal acid breakthrough: clinical significance and correlation with esophageal acid exposure
Am. J. Gastroenterol.
(2003)
S. Sanduleanu et al.
Changes in gastric mucosa and luminal environment during acid-suppressive therapy: a review in depth
Dig Liver Dis.
(2001)
D.R. Scott et al.
The role of internal urease in acid resistance of Helicobacter pylori
Gastroenterology
(1998)
A.F. Goddard et al.
Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice
Gastroenterology
(1996)
T. Lind et al.
The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies
Gastroenterology
(1999)
C.M. Beard et al.
Cancer after exposure to metronidazole
Mayo Clin. Proc.
(1988)
R.J. Adamek et al.
Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin-influence on treatment outcome
Am. J. Gastroenterol.
(1998)

M. Dojo et al.

Effects of CYP2C19 gene polymorphism on cure rates for Helicobacter pylori infection by triple therapy with proton pump inhibitor (omeprazole or rabeprazole), amoxycillin and clarithromycin in Japan

Dig Liver Dis.

(2001)

E. Bayerdorffer et al.

Double-blind trial of omeprazole and amoxicillin to cure Helicobacter pylori infection in patients with duodenal ulcers

Gastroenterology

(1995)

G. Sachs et al.

The pharmacology of the gastric acid pump: the H⁺, K⁺ ATPase

Annu. Rev. Pharmacol. Toxicol.

(1995)

R.A. Blum

Lansoprazole and omeprazole in the treatment of acid peptic disorders

Am. J. Health Syst. Pharm.

(1996)

S.P. Lockhart

Clinical review of lansoprazole

Br. J. Clin. Pract.

(1994)

H.D. Langtry et al.

Lansoprazole. An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders

Drugs

(1997)

C.I. Carswell et al.

Rabeprazole: an update of its use in acid-related disorders

Drugs

(2001)

P. Unge

Review of Helicobacter pylori eradication regimens

Scand J. Gastroenterol.

(1996)

M. Asaka et al.

A multicenter, double-blind study on triple therapy with lansoprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients

Helicobacter

(2001)

T. Furuta et al.

Effects of lansoprazole with or without amoxicillin on ulcer healing: relation to eradication of Helicobacter pylori

J. Clin. Gastroenterol.

(1995)

T. Andersson et al.

Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators

Ther. Drug Monit.

(1990)

T. Andersson et al.

Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects

Pharmacogenetics

(1992)

D.R. Sohn et al.

Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Oriental population

J. Pharmacol. Exp. Ther.

(1992)

R.E. Pearce et al.

Identification of the human P450 enzymes involved in lansoprazole metabolism

J. Pharmacol. Exp. Ther.

(1996)

H. Yamazaki et al.

Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples

J. Pharmacol. Exp. Ther.

(1997)

T. Ishizaki et al.

Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole

Aliment Pharmacol. Ther.

(1999)

A. Kupfer et al.

Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man

Eur. J. Clin. Pharmacol.

(1984)

M. Chang et al.

Interphenotype differences in disposition and effect on gastrin levels of omeprazole-suitability of omeprazole as a probe for CYP2C19

Br. J. Clin. Pharmacol.

(1995)

T. Kubota et al.

Genotyping of S-mephenytoin 4'-hydroxylation in an extended Japanese population

Clin. Pharmacol. Ther.

(1996)

T. Ishizaki et al.

Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals

Ther. Drug. Monit.

(1994)

Z.S. Xiao et al.

Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele

J. Pharmacol. Exp. Ther.

(1997)

H.G. Xie et al.

Genetic polymorphism of (S)-mephenytoin 4'-hydroxylation in populations of African descent

Br. J. Clin. Pharmacol.

(1999)

J.S. Marinac et al.

Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype

Clin. Pharmacol. Ther.

(1996)

C. Masimirembwa et al.

Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe

Clin. Pharmacol. Ther.

(1995)

S.M. de Morais et al.

Genetic analysis of the S-mephenytoin polymorphism in a Chinese population

Clin. Pharmacol. Ther.

(1995)

H.K. Roh et al.

CYP2C19 genotype and phenotype determined by omeprazole in a Korean population

Pharmacogenetics

(1996)

S.M. de Morais et al.

Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese

Mol. Pharmacol.

(1994)

T. Furuta et al.

CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans

Clin. Pharmacol. Ther.

(1999)

T. Furuta et al.

Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans

Clin. Pharmacol. Ther.

(1999)

T. Saitoh et al.

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

Aliment. Pharmacol. Ther.

(2002)

N. Shirai et al.

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Aliment Pharmacol. Ther.

(2001)

N. Shirai et al.

Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups

Aliment. Pharmacol. Ther.

(2002)

T. Furuta et al.

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19

Clin. Pharmacol. Ther.

(2001)

K.D. Bardhan et al.

Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group

Aliment Pharmacol. Ther.

(1995)

K.D. Bardhan

The role of proton pump inhibitors in the treatment of gastro-oesophageal reflux disease

Aliment Pharmacol. Ther.

(1995)

A. Kirchgatterer et al.

Current concepts in therapy of reflux disease

Wien Med. Wochenschr.

(2001)

T. Furuta et al.

Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole

Clin. Pharmacol. Ther.

(2002)

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ReviewInfluence of CYP2C19 Pharmacogenetic Polymorphism on Proton Pump Inhibitor-based Therapies

Summary:

Jpn. J. Pharmacol.

J. Biol. Chem.

Am. J. Gastroenterol.

Am. J. Gastroenterol.

Dig Liver Dis.

Gastroenterology

Gastroenterology

Gastroenterology

Mayo Clin. Proc.

Am. J. Gastroenterol.

Dig Liver Dis.

Gastroenterology

The pharmacology of the gastric acid pump: the H+, K+ ATPase

Annu. Rev. Pharmacol. Toxicol.

Lansoprazole and omeprazole in the treatment of acid peptic disorders

Am. J. Health Syst. Pharm.

Clinical review of lansoprazole

Br. J. Clin. Pract.

Lansoprazole. An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders

Drugs

Rabeprazole: an update of its use in acid-related disorders

Drugs

Review of Helicobacter pylori eradication regimens

Scand J. Gastroenterol.

A multicenter, double-blind study on triple therapy with lansoprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients

Helicobacter

Effects of lansoprazole with or without amoxicillin on ulcer healing: relation to eradication of Helicobacter pylori

J. Clin. Gastroenterol.

Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators

Ther. Drug Monit.

Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects

Pharmacogenetics

Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Oriental population

J. Pharmacol. Exp. Ther.

Identification of the human P450 enzymes involved in lansoprazole metabolism

J. Pharmacol. Exp. Ther.

Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples

J. Pharmacol. Exp. Ther.

Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole

Aliment Pharmacol. Ther.

Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man

Eur. J. Clin. Pharmacol.

Interphenotype differences in disposition and effect on gastrin levels of omeprazole-suitability of omeprazole as a probe for CYP2C19

Br. J. Clin. Pharmacol.

Genotyping of S-mephenytoin 4'-hydroxylation in an extended Japanese population

Clin. Pharmacol. Ther.

Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals

Ther. Drug. Monit.

Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele

J. Pharmacol. Exp. Ther.

Genetic polymorphism of (S)-mephenytoin 4'-hydroxylation in populations of African descent

Br. J. Clin. Pharmacol.

Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype

Clin. Pharmacol. Ther.

Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe

Clin. Pharmacol. Ther.

Genetic analysis of the S-mephenytoin polymorphism in a Chinese population

Clin. Pharmacol. Ther.

CYP2C19 genotype and phenotype determined by omeprazole in a Korean population

Pharmacogenetics

Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese

Mol. Pharmacol.

CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans

Clin. Pharmacol. Ther.

Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans

Clin. Pharmacol. Ther.

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

Aliment. Pharmacol. Ther.

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Aliment Pharmacol. Ther.

Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups

Aliment. Pharmacol. Ther.

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19

Clin. Pharmacol. Ther.

Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group

Aliment Pharmacol. Ther.

The role of proton pump inhibitors in the treatment of gastro-oesophageal reflux disease

Aliment Pharmacol. Ther.

Review
Influence of CYP2C19 Pharmacogenetic Polymorphism on Proton Pump Inhibitor-based Therapies

The pharmacology of the gastric acid pump: the H⁺, K⁺ ATPase