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PIII‐72
Author(s) -
Huh W.,
Jones D. R.,
Flockhart D. A.,
Desta Z.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.280
Subject(s) - ticlopidine , hydroxylation , clopidogrel , cytochrome p450 , pharmacology , cyp2d6 , efavirenz , chemistry , cyp2c19 , medicine , metabolism , biochemistry , enzyme , aspirin , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , family medicine
BACKGROUND Ticlopidine (TCL) and clopidogrel (CLP), a widely used thienopyridine antiplatelet drugs have been reported to inhibit CYP2B6 in vitro and in vivo. We have previously shown that the antiretroviral drug efavirenz is primarily metabolized by hepatic CYP2B6 and is proposed as probe of activity for this enzyme. We tested the ability of TCL and CLP to inhibit efavirenz metabolism in vitro. METHODS Enzyme reactions were carried out with human liver microsomes (HLMs) or expressed CYP2B6 and appropriate cofactors. A range of efavirenz concentrations was coincubated with HLMs with and without multiple concentrations of TCL and CLP to estimate K i values. In addition, other mechanisms of inhibition were tested by preincubating the test inhibitors of different times with HLMs and expressed CYP2B6. Similar inhibition experiments with bupropion (50 μM) served as positive controls. RESULTS CLP and TCL were potent noncompetitive inhibitors of efavirenz 8‐hydroxylation with HLMs (K i values: 2.6μM and 1.1 μM respectively). Preincubation experiments showed that CLP was a reversible inhibitor of efavirenz 8‐hydroxylation and a mechanism‐based inhibitor of bupropion hydroxylation, while TCL inhibited both substrates reversibly. CONCLUSIONS CLP and TCL are potent CYP2B6 inhibitors, but the mechanisms of inhibition might be substrate dependent. TCL and CLP may decrease efavirenz elimination in HIV patients and as a result increase its adverse effects. Clinical Pharmacology & Therapeutics (2005) 79 , P78–P78; doi: 10.1016/j.clpt.2005.12.280