PI-053

T. Tai, Q. Y. Mi, Y. Q. Pan, Q. Yin, H. G. Xie; Nanjing First Hospital, Nanjing Medical University, Nanjing, China

BACKGROUND: MRP3 (the gene product of ABCC3) is a sinusoidal efflux transporter that is predominantly expressed in the basolateral membrane of hepatocytes. Increased ABCC3 mRNA expression in peripheral white blood cells was seen in patient resistant to clopidogrel (CP). However, little is known about the mechanisms underlying this association.
METHODS: ABCC3 -/- mice (from the Netherlands Cancer Institute) and control mice, respectively, received the same dose of CP, and their blood samples were drawn and immediately mixed with the alkylating agent 2-bromo-3’-methoxyacetophenone to stabilize clopidogrel active metabolite (CAM) in plasma. Measurement of CP and CAM was performed by LC-MS/MS, and their pharmacokinetic parameters were determined with WinNonlin.
RESULTS: Compared with ABCC3 -/- mice, ABCC3 +/+ mice had a significant decrease in AUC (189.4 ± 14.9 vs. 363.7 ± 56.4 h• ng/mL; p < 0.001) and Cmax (146.2 ± 39.4 vs. 243.4 ± 28.7 ng/mL; p < 0.01), and a significant increase in CL/F (106.1 ± 8.4 vs. 56.0 ± 8.6 L/h/kg; p < 0.01) for CAM. Similarly, ABCC3 +/+ mice had significantly decreased AUC (197.3 ± 33.8 vs. 399.7 ± 29.0 h• ng/mL; p < 0.001) and increased CL/F (104.0 ± 20.7 vs. 50.2 ± 3.5 L/h/kg; p < 0.01) for CP.
CONCLUSION: The presence of MRP3 is associated with decreased formation and bioavailability of clopidogrel active metabolite, which can be used to explain why greater MRP3 expression is responsible for clopidogrel resistance in patient care.