title: Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor.
abstract: In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC50 of 200-400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 microM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 microM rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC50 values of 20.7, 1.6, and 3.1 microM using testosterone, midazolam, and felodipine as probe substrates, respectively. Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1.
authors.affiliation: Department of Pharmacokinetics, Pfizer Global Research and Development, Ann Arbor MI 48105, USA. jasminder.sahi@pfizer.com
authors.forename: Jasminder
authors.initials: J
authors.lastname: Sahi
authors.forename: Mark A
authors.initials: MA
authors.lastname: Milad
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rose
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.forename: Linda
authors.initials: L
authors.lastname: Stilgenbauer
authors.forename: Darryl
authors.initials: D
authors.lastname: Gilbert
authors.forename: Summer
authors.initials: S
authors.lastname: Jolley
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Stern
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000081:Acetamides; D000085:Acetates / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000081:Acetamides; D000085:Acetates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam