COMMENT: Only in the last year has a new allele of CYP2C19 been recognized. CYP2C19*17 is associated with ultrarapid metabolizer status. Omeprazole is not only a probe drug for this CYP, but it is a widely used PPI throughout the world. The fact that individual who are homozygotic for this allele will have 2.1-fold lower concentration of omeprazole as shown by the study abstracted below is highly significant and can be associated with therapeutic failure. This is also likely to be significant for other drugs that use CYP2C19 as their major metabolic pathway.A recent study of clopidogrel showed the importance of heterozygous and poor metabolizer status on blood levels and it is only a matter of time before ultraextensive CYP2C19 metabolizer will be shown to have decreased levels of clopidogrel. Other CYP2C19 substrates such as citalopram, moclobemide, carisoprodol may be affected. Prodrugs that are metabolized to their active metabolite: cyclophosphamide, ifosphosphomide and proguanil will have increased levels in CYP2C19 ultrarapid metabolzers. It is not currently known how common this allele is. Stay tuned for more on CYP2C19*17
ABSTRACTS:Br J Clin Pharmacol. 2008 Feb 20Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers.Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M, Eliasson E, Bertilsson L Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet and Division of Clinical Pharmacology, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. * The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios.
WHAT THIS STUDY ADDS
This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. * The observed differences in omeprazole AUC(infinity) suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure.
To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers.METHODSIn a single-dose pharmacokinetic study, 17healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography.
The mean omeprazole AU (infinity) of 1973 h nmol l(-1) in CYP2C19*17/*17 subjects was 2.1fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l(-1), P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC(infinity) of 1083 h nmol l(-1), 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l(-1), P =0.03). A pronounced correlation (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) values.
The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure. PMID: 18294333Clin Pharmacol Ther. 2008 Mar 5The Effect of CYP2C19 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Clopidogrel: A Possible Mechanism for Clopidogrel Resistance.Kim K, Park P, Hong S, Park JY.Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Korea.We evaluated the effect of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamcis of clopidogrel. Twenty-four subjects were divided into three groups on the basis of their CYP2C19 genotype: homozygous extensive metabolizers (homoEMs, n = 8), heterozygous EMs (heteroEMs, n = 8), and poor metabolizers (PMs, n = 8).
After a single 300-mg loading dose of clopidogrel on day 1, followed by a 75-mg daily maintenance dose from days 2 to 7, we measured the plasma levels of clopidogrel and assessed the antiplatelet effect as pharmacodynamics. The mean clopidogrel area under the curve (AUC) for PMs was 1.8- and 2.9-fold higher than that for heteroEMs and homoEMs, respectively (P = 0.013). The mean peak plasma concentration in PMs was 1.8- and 4.7-fold higher than that of heteroEMs and homoEMs, respectively (P = 0.008). PMs exhibited a significantly lower antiplatelet effect than heteroEMs or homoEMs (P < 0.001). From these findings it is clear that the CYP2C19 genotype affects the plasma levels of clopidogrel and modulates the antiplatelet effect of clopidogrel. PMID 18323861.
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