Human P450 metabolism of warfarin

Kaminsky, Laurence S.; Zhang, Zhiyi

doi:10.1016/s0163-7258(96)00140-4

Cited by 734 publications

(571 citation statements)

References 41 publications

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“…(R)-warfarin is mainly metabolized by CYP1A2 and CYP3A4, while (S)-warfarin, the pharmacologically more active enantiomer, is primarily metabolized by CYP2C9. Due to the narrow therapeutic window of warfarin, special attention should be paid to the magnitude of metabolic drug-drug interaction (DDI) with warfarin [17]. Previous investigations have shown that many drugs that inhibit CYP3A4 and CYP2C9 could augment the anticoagulant effect of warfarin [21,22].…”

Section: Discussionmentioning

confidence: 99%

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Fang

Zhang

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug-drug interaction (DDI) existed when warfarin was co-administered with noscapine.• In vitro testing with recombinant human enzyme showed that noscapine inhibited CYP3A4 and CYP2C9 with an IC50 of around 1 mM.• However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS• Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9.• DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical noscapine-warfarin interaction. AIMSTo investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. METHODSThe activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co-or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. RESULTSAmong seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50 of 10.8 Ϯ 2.5 mM and 13.3 Ϯ 1.2 mM. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with Ki value of 8.8 mM, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with Ki value of 5.2 mM. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 mM and 0.06 min -1 for CYP3A4 and 8.9 mM and 0.014 min -1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using Cmax or 0.5% and 0.4% using unbound Cmax with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. CONCLUSIONSTDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.

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Section: Discussionmentioning

confidence: 99%

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Fang

Zhang

et al. 2010

Brit J Clinical Pharma

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“…For instance, polymorphisms in CYP1A1 [68] and CYP3A5 [69] , enzymes that metabolize (R)-warfarin, are clinically insignificant because of the minimal effects of (R)-warfarin on anticoagulation. Genes in the vitamin K regeneration cycle and vitamin K-dependent clotting factors have also been studied, including CYP2C18, CYP2C19, PROC (Protein C), ABCB1, APOE (apolipoprotein E), EPHX1 (epoxide hydrolase 1 gene), CALU (calumenin), GGCX (gamma-glutamyl carboxylase), ORM1 (orosomucoid 1), ORM2, vitamin K-dependent clotting factor II (prothrombin), VII, IX, and X and PXR [67,[69][70][71][72][73][74] .…”

Section: Warfarinmentioning

confidence: 99%

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

Shu

Wang

et al. 2015

Acta Pharmacol Sin

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“…15 Warfarin is administered as a racemate that consists of R-and S-enantiomers, the S-form being three to five times more active than the R form. 16,17 S-warfarin is metabolised by the cytochrome P450 enzyme CYP2C9, 18 and genetic variability in CYP2C9 partly explains the large differences in the required warfarin dose. 15 Two variants that encode enzymes with single amino-acid substitutions, CYP2C9*2 and CYP2C9*3, are associated with a significant decrease in warfarin dose requirement, especially among Europeans.…”

Section: Introductionmentioning

confidence: 99%

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

et al. 2005

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We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

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Human P450 metabolism of warfarin

Cited by 734 publications

References 41 publications

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

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