Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Desta, Zeruesenay; Zhao, Xiaojiong; Shin, Jae-Gook; Flockhart, David A.

doi:10.2165/00003088-200241120-00002

Cited by 942Pharmacogenetics and Drug MetabolismGenetic Associations and EpidemiologyAntiplatelet Therapy and Cardiovascular Diseases

Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Desta, Zeruesenay, Zhao, Xiaojiong, Shin, Jae-Gook, Flockhart, David A.·2002·Clinical Pharmacokinetics

DOI 10.2165/00003088-200241120-00002

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Abstract

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs fo…

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The prevalence of poor metabolisers of CYP2C19 in Caucasian people is 1-3%.
“As the prevalence of PMs in Caucasian people is 1–3%, in some cases, the CgA could still be false positive after 2 weeks of discontinuation.”
From Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours (2011) · cites this paper as Desta et al, 2002
In some cases, chromogranin A could still be false positive after 2 weeks of discontinuation.
“As the prevalence of PMs in Caucasian people is 1–3%, in some cases, the CgA could still be false positive after 2 weeks of discontinuation.”
From Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours (2011) · cites this paper as Desta et al, 2002
Even a five-fold higher exposure to proton pump inhibitors has been observed in poor metabolisers than in extensive metabolisers of CYP2C19.
“Even a five-fold higher exposure to PPIs has been observed in poor metabolisers (PMs) than in extensive metabolisers of CYP2C19 (Desta et al, 2002; Giusti et al, 2004).”
From Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours (2011) · cites this paper as Desta et al, 2002

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Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation
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“Even a five-fold higher exposure to PPIs has been observed in poor metabolisers (PMs) than in extensive metabolisers of CYP2C19 (Desta et al, 2002; Giusti et al, 2004).”
Background

The Influence of Combined CYP2D6 and CYP2C19 Genotypes on Venlafaxine and O-Desmethylvenlafaxine Concentrations in a Large Patient Cohort
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150 THE ROLE OF CYP2D6 AND CYP2C19 IN THE STEREOSELECTIVE METABOLISM OF THIORIDAZINE IN PATIENTS
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Authors: Desta, Z., Zhao, X., Shin, J.-G., & Flockhart, D. A.
Affiliations: Indiana University Hospital (US)
Indiana University School of Medicine (US)
Corresponding author: Flockhart, David A.
ORCID: Desta, Zeruesenay
Shin, Jae-Gook
Venue: Clinical Pharmacokinetics
Publisher: Springer Science and Business Media LLC
Published: 2002
Volume: 41
Issue: 12
Pages: 913-958
ISSN: 0312-5963 (ISSN-L)
DOI: 10.2165/00003088-200241120-00002
OpenAlex: W2012407966
Cited by: 942
References: 358
Citations by year: 2026: 17 · 2025: 15 · 2024: 16 · 2023: 33 · 2022: 26 · 2021: 19 · 2020: 47 · 2019: 28 · 2018: 34 · 2017: 37 · 2016: 46 · 2015: 46 · 2014: 52 · 2013: 59 · 2012: 61
FWCI: 22.68
Type: journal article
Language: en
Open access: closed
Locations: Clinical Pharmacokinetics (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5u01gm061373-10)
National Institute of General Medical Sciences (U01GM61373-01, T32GM008386, R01-GM 56878-01)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
Keywords: CYP2C19, genetic polymorphism, pharmacogenetics, pharmacokinetics, mephenytoin, proton pump inhibitors, omeprazole, lansoprazole, pantoprazole, CYP3A, phenytoin, tricyclic antidepressants, drug interactions, enzyme inhibition, enzyme induction, Helicobacter pylori infection, reflux disease
MeSH terms: Animals, Anticonvulsants, Antidepressive Agents, Aryl Hydrocarbon Hydroxylases, Humans, Mixed Function Oxygenases, Pharmacogenetics, Polymorphism, Genetic, Substrate Specificity, Proton Pumps, Proton Pump Inhibitors, Cytochrome P-450 CYP2C19

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Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

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