Effect of Omeprazole on the Hydroxylation of Warfarin Enantiomers in Human: In-Vitro Studies with Liver Microsomes and cDNA-Expressed Cytochrome P450 Isozymes
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.Current Drug Metabolism (Impact Factor: 2.98). 11/2005; 6(5):399-411. DOI: 10.2174/138920005774330620
Clinically observed warfarin-omeprazole interaction has been found to be associated with the inhibition of R-warfarin hydroxylation by omeprazole. The present study was conducted in human liver microsomes and cDNA-expressed cytochrome P450s to assess the inhibitory potential of omeprazole on the hydroxylation of warfarin enantiomers, and to identify the cytochrome P450 isozymes involved in the inhibition of hydroxylation of warfarin enantiomers by omeprazole, and to evaluate the extent to which the in vitro data is predictive of the actual pharmacokinetic interaction between warfarin and omeprazole observed in vivo. Omeprazole inhibited the formation of R-6-, R-7- and S-7-hydroxywarfarin with the Ki values of 40, 22 and 116 microM, respectively. Its inhibitory effect was selective towards R-warfarin. Further study conducted in cDNA-expressed cytochrome P450s (CYPs) demonstrates that the inhibition of the in-vitro biotransformation of warfarin enantiomers by omeprazole is attributed to its inhibitory effect on the activities of CYP1A2, CYP3A4, CYP2C9 and CYP2C19. The extent of the in vivo warfarin-omeprazole interaction was underestimated as based on the Ki values obtained from the in-vitro inhibition study, suggesting an underestimation of the effective concentration of the inhibitor at the site of interaction or some other mechanisms involved in the drug interaction between warfarin and omeprazole.
- Personalized Medicine 08/2007; 4(3):321-328. DOI:10.2217/174105188.8.131.521 · 1.34 Impact Factor
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ABSTRACT: The aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of warfarin enantiomers in relation to cytochrome P450 2C19 (CYP2C19) genotypes. Fourteen subjects, of whom seven were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled. After a single oral 10 mg dose of racemic warfarin, the plasma concentrations of the warfarin enantiomers and prothrombin time expressed as international normalized ratio (PT-INR) were measured over the course of 120 h. The mean plasma concentrations and elimination half-life of (R)-warfarin of all the subjects were about 2-fold greater than those of (S)-warfarin. Additionally, the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) and the elimination half-life of (R)-warfarin in PMs were significantly greater than those in hmEMs (P = 0.0005 and P = 0.0101 respectively). The S/R ratios of AUC of warfarin enantiomers were 0.51 in hmEMs and 0.37 in PMs (P = 0.0052). Whereas no difference was found in all pharmacokinetic parameters of (S)-warfarin in hmEMs compared with PMs. No significant difference in PT-INR, used as a measure of anticoagulant effect, was found between the hmEMs and PMs. These results show that CYP2C19 activity is important in the pharmacokinetics of (R)-warfarin. However, when warfarin is administered as a racemate, this difference is not translated into any significant effect in the pharmacodynamics of warfarin.Journal of Clinical Pharmacy and Therapeutics 03/2008; 33(1):67-73. DOI:10.1111/j.1365-2710.2008.00887.x · 1.67 Impact Factor
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ABSTRACT: Oral anticoagulants (OA) are a leading cause of fatal haemorrhagic adverse events in relation with an important interindividual variability of response to these drugs. Besides several clinical factors, this interindividual variability of response to OA has a pharmacogenetic basis. Carriers of cytochrome P450 2C9 (CYP2C9)-deficient alleles have a reduced clearance of warfarin and are exposed to dramatic overdoses in the first weeks of treatment. Genetic polymorphisms of vitamin K epoxide reductase (VKORC1), the target of OA, identify patients with a high sensitivity to OA who are at risk of early overdose. Most pharmacogenetic evidence is presently restricted to warfarin. Several warfarin dosing algorithms have been constructed, adapted on CYP2C9 and VKORC1 genotypes and clinical factors, to predict the best dose for each patient. Carriers of one of allelic variant need a 20-30% reduction of warfarin dose. However, definite evidence concerning the usefulness of these algorithms in terms of reducing the frequency of major bleeding episodes is still lacking. Ongoing prospective randomised trials will ascertain definitive answer over the coming years.European Journal of Clinical Pharmacology 09/2008; 64(10):953-60. DOI:10.1007/s00228-008-0542-2 · 2.97 Impact Factor
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