RT Journal Article
SR Electronic
T1 Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1027
OP 1034
DO 10.1124/jpet.103.050526
VO 306
IS 3
A1 Sahi, Jasminder
A1 Milad, Mark A.
A1 Zheng, Xianxian
A1 Rose, Kelly A.
A1 Wang, Hongbing
A1 Stilgenbauer, Linda
A1 Gilbert, Darryl
A1 Jolley, Summer
A1 Stern, Ralph H.
A1 LeCluyse, Edward L.
YR 2003
UL http://jpet.aspetjournals.org/content/306/3/1027.abstract
AB 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 μM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 μM 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 μM 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. The American Society for Pharmacology and Experimental Therapeutics