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Research ArticleArticle

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

Jasminder Sahi, Ralph H. Stern, Mark A. Milad, Kelly A. Rose, Gordon Gibson, Xianxian Zheng, Linda Stilgenbauer, Nalini Sadagopan, Summer Jolley, Darryl Gilbert and Edward L. LeCluyse
Drug Metabolism and Disposition December 2004, 32 (12) 1370-1376; DOI: https://doi.org/10.1124/dmd.104.000208
Jasminder Sahi
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Ralph H. Stern
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Mark A. Milad
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Kelly A. Rose
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Gordon Gibson
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Xianxian Zheng
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Linda Stilgenbauer
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Nalini Sadagopan
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Summer Jolley
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Darryl Gilbert
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Edward L. LeCluyse
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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 β-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 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.

Footnotes

  • doi:10.1124/dmd.104.000208.

  • ABBREVIATIONS: AUC, area under the curve; MDR1, multiple drug resistance protein 1; PXR, pregnane X receptor; ITS+, insulin/transferrin/selenium; BCIP/NBT, 5-bromo-4-chloroindolyl-phosphatase/nitrobenzotetrazolium; HPLC, high-performance liquid chromatography; HLM, human liver microsomes; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; LC/MS/MS, liquid chromatography-tandem mass spectrometry; PT, prothrombin time; P450, cytochrome P450; β-NF, β-naphthoflavone; 3-MC, 3-methylcholanthrene.

    • Received April 16, 2004.
    • Accepted August 24, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (12)
Drug Metabolism and Disposition
Vol. 32, Issue 12
1 Dec 2004
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Research ArticleArticle

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

Jasminder Sahi, Ralph H. Stern, Mark A. Milad, Kelly A. Rose, Gordon Gibson, Xianxian Zheng, Linda Stilgenbauer, Nalini Sadagopan, Summer Jolley, Darryl Gilbert and Edward L. LeCluyse
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1370-1376; DOI: https://doi.org/10.1124/dmd.104.000208

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Research ArticleArticle

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

Jasminder Sahi, Ralph H. Stern, Mark A. Milad, Kelly A. Rose, Gordon Gibson, Xianxian Zheng, Linda Stilgenbauer, Nalini Sadagopan, Summer Jolley, Darryl Gilbert and Edward L. LeCluyse
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1370-1376; DOI: https://doi.org/10.1124/dmd.104.000208
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