RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 529
OP 534
DO 10.1124/dmd.107.018853
VO 36
IS 3
A1 Masakatsu Kotsuma
A1 Taro Tokui
A1 Tomoko Ishizuka-Ozeki
A1 Tomoyo Honda
A1 Haruo Iwabuchi
A1 Takahiro Murai
A1 Toshihiko Ikeda
A1 Hideo Saji
YR 2008
UL http://dmd.aspetjournals.org/content/36/3/529.abstract
AB 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