Title:Influence of CYP2C9 Polymorphisms on Plasma Concentration of Warfarin and
7-Hydroxy Warfarin in South Indian Patients
Volume: 22
Issue: 12
Author(s): Dhakchinamoorthi Krishna Kumar*, Chakradhara Rao Satyanarayana Uppugunduri, Deepak Gopal Shewade, Sai Chandran B.V. and Chandrasekaran Adithan
Affiliation:
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India
Keywords:
Warfarin, metabolic ratio, CYP2C9, genetic variants, metabolism, HPLC, South Indian.
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.