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CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528

Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan (M.K., T.T., T.I.-O., T.H., H.I., T.M., T.I.); and Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan (H.S.)

Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor. We conducted metabolic studies of pactimibe and its plasma metabolite, R-125528. Pactimibe had multiple metabolic pathways including indolin oxidation to form R-125528, -1 oxidation, N-dealkylation, and glucuronidation. Among them, the indolin oxidation and the -1 oxidation were dominant and were mainly catalyzed by CYP3A4 and CYP2D6, respectively. The intrinsic clearance (CL_int) values for these pathways in human hepatic microsomes were 0.63 and 0.76 µl/min/mg-protein, respectively. On the other hand, the metabolic reaction for R-125528 was restricted. It was demonstrated that -1 oxidation was the only pathway that could eliminate R-125528 from the systemic circulation. To our surprise, only CYP2D6-expressing microsomes could catalyze the reaction, and -1 oxidation was strongly correlated with the CYP2D6 marker reaction, dextromethorphan O-demethylation (r² = 0.90), in human hepatic microsomes. Although R-125528 is an atypical substrate for CYP2D6 because of its acidity, the K_m value was 1.8 µM for the reaction in human hepatic microsomes and the CL_int value was as high as 75.0 µl/min/mg-protein. These results suggested that the systemic clearance of R-125528 was highly dependent on CYP2D6 activity and that several studies with CYP2D6 including drug-drug interaction and polymorphism sensitivity should be performed during development from the viewpoint of metabolite safety assessment. The finding that R-125528, an acidic compound devoid of basic nitrogen, was a good substrate for CYP2D6 raised a question about previously reported CYP2D6 models based on a critical electrostatic interaction with Asp³⁰¹ and/or Glu²¹⁶.

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				M. Kotsuma, H. Hanzawa, Y. Iwata, K. Takahashi, and T. Tokui Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528 Drug Metab. Dispos., September 1, 2008; 36(9): 1938 - 1943. [Abstract] [Full Text] [PDF]

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