PII-048 - INTERETHNIC DIFFRENCE IN (S)-WARAIN PHARMACOKINETICS AND EXTENT OF ANTICOAGULATION BETWEEN ETHIOPIAN AND NON-ETHIOPIAN JEWS.

m. wanounou¹, Y. Caraco¹, C. Shaul², Z. Abu Ghosh¹, S. Blotnick¹, m. Bialer³; ¹Hadassah-Hebrew University Medical Center, Jerusalem, Israel, ²Shaary-Zedek Medical Center, Jerusalem, Israel, ³The Hebrew University of Jerusalem, Jerusalem, Israel.

Background: Previous study demonstrated a 30% decrease in Phenytoin Metabolic Ratio (PMR), a marker to CYP2C9 catalytic activity, among Ethiopian Jews ancestry (EJA) vs non-Ethiopian Jews (NEJ) carriers of the CYP2C9*1/*1 genotype.
Objective of current study- Evaluate whether the same difference exists for (S)-warfarin, a prototype of narrow therapeutic window drug and a CYP2C9 substrate.

Methods: A single warfarin dose (20 mg) was administered to Ethiopian (n=127) and non-Ethiopian (n=79) Jews, all carriers of the CYP2C9*1/*1 (none CYP2C9*2,*5,*8,*6 and *11) genotype. Post dosing, periodic blood samples were obtained over a period of 120 hours. (S)-warfarin plasma concentration was measured an enantioselective HPLC method and INR was monitored throughout the study period.

Results: Mean oral clearance of (S) -Warfarin was decreased by approximately 13 % in the EJA group as compared to the NEJ group (178 ± 75 vs. 202± 43 mL/h, respectively, p< 0.001).
Among carriers of the Asp/Asp (D36Y; rs61742245) genotype, INR AUC0→120 was significantly increased in the EJA as compared to NEJ irrespective of the VKORC1 genotype (AA: 205±33 vs 181±17 h, p< 0.01; AB: 171±19 vs. 158±17 h, p< 0.003; BB: 158±17 vs. 147±13 h, p< 0.01).

Conclusion: Among carriers of the wild-type genotype, the activity of CYP2C9 is significantly reduced among Ethiopian as compared to non-Ethiopian Jews. This difference confirms our previous findings using phenytoin as a prob CYP2C9 substrate. The reason for this interethnic difference in the catalytic activity is currently unclear. Dietary causes, yet undefined polymorphism, expression and epigenetic factors may offer possible explanation to the described difference and require further investigation.