TY - JOUR T1 - CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 529 LP - 534 DO - 10.1124/dmd.107.018853 VL - 36 IS - 3 AU - Masakatsu Kotsuma AU - Taro Tokui AU - Tomoko Ishizuka-Ozeki AU - Tomoyo Honda AU - Haruo Iwabuchi AU - Takahiro Murai AU - Toshihiko Ikeda AU - Hideo Saji Y1 - 2008/03/01 UR - http://dmd.aspetjournals.org/content/36/3/529.abstract N2 - 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, ω-1 oxidation, N-dealkylation, and glucuronidation. Among them, the indolin oxidation and the ω-1 oxidation were dominant and were mainly catalyzed by CYP3A4 and CYP2D6, respectively. The intrinsic clearance (CLint) 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 ω-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 ω-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 Km value was 1.8 μM for the reaction in human hepatic microsomes and the CLint 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. The American Society for Pharmacology and Experimental Therapeutics ER -