Comparison of CYP2C9 activity between Ethiopian and non-Ethiopian Jews: an interethnic study of (S)-warfarin pharmacokinetic and pharmacodynamic

Introduction – CYP2C9 is characterized by marked interindividual variability. A significant fraction of this variability is attributed to ethnic specific genetic polymorphisms. We have recently shown that the activity of CYP2C9 as measured by phenytoin metabolic ratio is decreased by 30% among Ethiopians as compared to non-Ethiopians Jews carriers of CYP2C9*1/*1 genotype. The purpose of the current study was to evaluate whether similar difference exists in the pharmacokinetics of (S)-warfarin, a prototype substrate of CYP2C9. Validating this systemic reduction through robust in vivo pharmacokinetic profiling is critical for safely guiding the use of narrow-therapeutic-index drugs. Furthermore, these findings address the recognized genomic diversity gap, providing essential precision dosing foundations for this cohort while serving as a vital proxy for the underrepresented broader Ethiopian population. Methods – Single dose of warfarin (20 mg) was administered to 150 Ethiopians and 180 non-Ethiopian healthy, non-smokers subjects. CYP2C9 activity was assessed by (S)-warfarin oral clearance and INR was monitored for 120 h post-dose. CYP2C9 genotyping was performed by direct sequencing. Results – CYP2C9 genotype correlated with the (S)-warfarin oral clearance in both ethnic groups (p < 0.001). Despite the predominance of CYP2C9*1/*1 genotype in the Ethiopian group, (S)-warfarin oral clearance was reduced by 12.3% as compared to the non-Ethiopian (p < 0.001). Comparison limited to carriers of CYP2C9*1/*1 genotype yielded higher difference of 15.3% (p < 0.001). Stratified VKORC1 genotype analysis revealed significantly greater pharmacodynamic effect in Ethiopians as compared to non-Ethiopians carrying VKORC1 AB and BB haplotypes (AUCINR120: p < 0.04 and p < 0.004 respectively; INRMAX: p < 0.03 and p < 0.002, respectively). Conclusion – CYP2C9 activity is modestly reduced in Ethiopians as compared to non-Ethiopians thus corroborating our findings regrading phenytoin metabolism. Ethiopian Jews may be susceptible to experience adverse effects when administered CYP2C9 substrate characterized by a narrow therapeutic window. The cause for decreased CYP2C9 activity in Ethiopians is currently under investigation.