RT Journal Article
SR Electronic
T1 SELECTIVE INHIBITION OF CYP2B6-CATALYZED BUPROPION HYDROXYLATION IN HUMAN LIVER MICROSOMES IN VITRO
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 626
OP 631
DO 10.1124/dmd.32.6.626
VO 32
IS 6
A1 Turpeinen, Miia
A1 Nieminen, Riina
A1 Juntunen, Tarja
A1 Taavitsainen, Päivi
A1 Raunio, Hannu
A1 Pelkonen, Olavi
YR 2004
UL http://dmd.aspetjournals.org/content/32/6/626.abstract
AB Some inhibitory agents against CYP2B6 have been reported, but none of these has been extensively characterized or compared with others, as to the potency and selectivity of inhibition toward CYP2B6. The goal of this work was to find a selective and potent chemical in vitro inhibitor toward CYP2B6 using bupropion hydroxylation as a model reaction. At the initial screening of more than 30 substances, ticlopidine, triethylenethiophosphoramide (thioTEPA), metyrapone, xanthate C8, and benzylisothiocyanate displayed IC50 values of <10 μM and were selected for a more detailed analysis. Metyrapone, xanthate C8, and benzylisothiocyanate inhibited several other cytochrome P450 activities rather effectively, some of them even more potently than CYP2B6, and consequently are unsuitable as CYP2B6-selective probes. Ticlopidine and thioTEPA were the most potent inhibitors of bupropion hydroxylation with Ki values of 0.2 and 2.8 μM, respectively. The inhibition type of ticlopidine was found to be mixed type, with a component of mechanism-based inhibition, whereas thioTEPA inhibited CYP2B6 in a competitive manner. In addition to CYP2B6, ticlopidine also inhibited both mephenytoin 4-hydroxylation (CYP2C19) (IC50, 2.7 μM) and dextromethorphan O-demethylation (CYP2D6) (IC50, 4.4 μM). For thioTEPA the next sensitive P450 activity after CYP2B6 was coumarin 7-hydroxylation (IC50, 256 μM). Thus, although both compounds proved to be relatively potent inhibitors of CYP2B6, thioTEPA was about 2 orders of magnitude more selective than ticlopidine. Thus, thioTEPA is a drug of choice when high CYP2B6 selectivity among major P450 enzymes is required. Ticlopidine is a useful alternative under a controlled experimental setup and when higher potency is needed. The American Society for Pharmacology and Experimental Therapeutics