title: Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.
abstract: Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. 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 coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-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 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg of 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Jasminder.Sahi@Pfizer.com
authors.forename: Jasminder
authors.initials: J
authors.lastname: Sahi
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Stern
authors.forename: Mark A
authors.initials: MA
authors.lastname: Milad
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rose
authors.forename: Gordon
authors.initials: G
authors.lastname: Gibson
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.forename: Linda
authors.initials: L
authors.lastname: Stilgenbauer
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: Summer
authors.initials: S
authors.lastname: Jolley
authors.forename: Darryl
authors.initials: D
authors.lastname: Gilbert
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
mesh_terms: D000081:Acetamides; D000085:Acetates / Q000494:pharmacology*; D000925:Anticoagulants / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D000077297:Pregnane X Receptor; D011517:Prothrombin Time; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D000081:Acetamides; D000085:Acetates; D000925:Anticoagulants; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D002785:Sterol O-Acyltransferase