Received for publication April 16, 2004.
Revised August 23, 2004.
Accepted for publication August 24, 2004.

EFFECTS OF AVASIMIBE ON CYTOCHROME P450 2C9 EXPRESSION IN VITRO AND IN VIVO

Abstract

Avasimibe, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, has been previously shown to be a potent inducer of CYP3A4 and MDR1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be co-administered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting and activity assays, using rifampicin and -naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9 and CYP2B6 immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC50 2.9 µM), CYP1A2 (IC₅₀ 13.9 µM) and CYP2C19 (IC₅₀ 26.5 µM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin

Key words: clinical pharmacokinetics, CYP induction, CYP inhibition, CYP1A, CYP2C, drug development, drug-drug interactions, hepatocytes, isolated hepatocytes