KeywordsCYP2C9, CYP4F2, Chinese, mechanical heart valve replacement, VKORC1, warfarin ---------------------------------------------------------------------- Received WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Genetic polymorphisms of VKORC1 and CYP2C9 are known to influence warfarin dosage.• Recent studies among Caucasians showed that polymorphisms of CYP4F2 also play a role in warfarin pharmacogenetics.• The contribution of CYP4F2 variants to the variability inwarfarin dose requirement in Chinese subjects remains to be investigated. WHAT THIS STUDY ADDS• This research was to study the effect of CYP4F2 variants on warfarin requirements in the Han Chinese population.• This study developed a multiple regression model including CYP2C9, VKORC1 3673G>A, CYP4F2 genotypes and age, weight, combination use of amiodarone which could explain 56.1% of the individual variability in warfarin dose CYP4F2 could explain 4% of the variance in warfarin dose.• We found that one novel genotypic polymorphism 5417G>T for Asp36Tyr, which was identified as an important marker of warfarin resistance, was absent in the Han Chinese population in our study. AIMSThe objective of this study was to assess the effect of the CYP4F2 on the daily stable warfarin dose requirement in Han Chinese patients with mechanical heart valve replacement (MHVR). METHODS From March 2007 to November 2008, 222Han Chinese MHVR patients were recruited in our study. VKORC1 3673G>A, 5417G>T, CYP2C9 *3 and CYP4F2 rs2108622 were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Polymorphisms of VKORC1 9041G>A were detected by direct sequencing. Multiple linear regression analysis was used to investigate the contribution of CYP4F2. RESULTSThe CYP4F2 rs2108622 CT/TT group took a significantly higher stable warfarin dose (3.2 mg day CONCLUSIONCYP4F2 is a minor significant factor of individual variability in the stable warfarin dose in Han Chinese patients with MHVR. The effect of CYP2C9 and VKORC1 genotypes on variability in the stable warfarin dose had also been confirmed.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

Low-dose methotrexate is the first-line therapy for juvenile idiopathic arthritis. In vivo, methotrexate is converted into a series of methotrexate polyglutamates whose intracellular levels contribute significantly to its efficacy and toxicity. In this study, a novel high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine erythrocyte methotrexate polyglutamates using stable isotope-labeled internal standards. Erythrocyte samples were precipitated by perchloric acid and then determined on an XBridge BEH C18 column with an XP vanguard precolumn in 12 min. The mobile phase consisted of 10 nM ammonium acetate (pH 10) and methanol under gradient elution. The detection was carried out in multiple reaction monitoring mode via an electrospray ionization source in positive ionization mode. The calibration curve for each metabolite was linear from 2.0 to 500.0 nmol/L (r 2 > 0.99). The intraday and interday accuracies were between 93.0 and 107.0%, and the corresponding precisions were between 0.8 and 5.2%.The relative recovery ranged from 82.7 to 105.1%, and the relative matrix effect varied from 96.5 to 104.4%. The erythrocyte metabolites were stable for 30 days at −80 • C. This simple and accurate method is applicable to routine monitoring

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