ABSTRACT
BACKGROUND: Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin. OBJECTIVES: The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.6±11.6 (SD) years; male to female ratio 81:129). METHODS: High-performance liquid chromatography (HPLC) with UV detector was used to measure plasma concentrations of warfarin and 7-hydroxy warfarin. Plasma samples were collected 12 h after the previous dose of warfarin was administered. CYP2C9 variants (rs1799853 and rs1057910) were identified using real-time polymerase chain reaction allele-discrimination method. RESULTS: The mean daily maintenance dose of warfarin was 4.6±1.8 (SD) mg. The mean plasma warfarin and 7-hydroxy warfarin concentrations were 3.7±1.6 (SD) µg/mL and 1.1±0.54 (SD) µg/mL, respectively. Patients carrying other CYP2C9 variants required 39% lower warfarin maintenance dose 3.3±1.2(SD)mg than CYP2C9*1*1 carrier 4.9±1.8(SD)mg, (p<0.0001). MRs differed significantly between CYP2C9 variant carriers (8.1±5.1) and normal genotype carriers (4.8±3.9) (p<0.0001). Probit analysis identified an MR value of 7.6 as the anti-mode (sensitivity of 84% and specificity of 55%) to differentiate poor and intermediate metabolizers (carriers of any CYP2C9*2 or CYP2C9*3 variants) from normal metabolizers (CYP2C9*1*1 genotype). CONCLUSION: The present study results provide, insights on the effect of CYP2C9 genetic polymorphisms on inter-individual variability in warfarin metabolism and emphasizes utility of phenotyping in a setting of genotype-guided dosing of warfarin in South Indian population.
Subject(s)
Cytochrome P-450 CYP2C9/genetics , Warfarin/analogs & derivatives , Anticoagulants/blood , Anticoagulants/pharmacokinetics , Asian People/genetics , Biological Variation, Population/genetics , Chromatography, High Pressure Liquid/methods , Dose-Response Relationship, Drug , Female , Humans , India , Male , Middle Aged , Pharmacogenomic Testing/methods , Polymorphism, Single Nucleotide , Retrospective Studies , Warfarin/blood , Warfarin/pharmacokineticsABSTRACT
This is a case of a 9-year-old boy with a congenital arteriovenous malformation (AVM) of the right upper extremity arising from the right subclavian artery. He underwent open surgical excision of the vascular tumor. Upon reviewing the literature, a high incidence of right-sided congenital AVM of the proximal upper extremity was identified. It has been suggested that this high incidence may be related to the complexity of the embryologic development of the right subclavian artery.
