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Received for publication February 17, 2003.
Revised March 18, 2003.
Accepted for publication May 22, 2003.
In vitro and clinical studies were conducted to characterize the potential of avasimibe, an ACAT inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed following 50 mg and 750 mg avasimibe daily for 7 days, respectively. A 40% decrease in digoxin AUC (P-glycoprotein substrate) was observed with 750 mg 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 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 to 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 µM, 1.6 µM and 3.1 µM using testosterone, midazolam and felodipine as probe substrates, respectively. CYP3A4 inhibition is not observed in the clinical studies. 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 MDR1.
Key words:
Avasimibe, CYP3A4, MDR1, PXR, clinical, induction
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