Received for publication October 18, 2007.
Revised November 20, 2007.
Accepted for publication November 30, 2007.

CYP2D6 mediated metabolism of a novel ACAT inihibitor, pactimibe, and its unique plasma metabolite, R-125528

Abstract

Pactimibe sulfate is a novel ACAT 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 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 -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 due to 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 conducted 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.

Key words: CYP2D, drug-drug interactions, genetic polymorphism

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