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MECHANISM-BASED INHIBITION OF HUMAN LIVER MICROSOMAL CYTOCHROME P450 1A2 BY ZILEUTON, A 5-LIPOXYGENASE INHIBITOR

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (P.L., M.L.S., D.E.S., M.S., A.D.R.); and Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey (C.E.R.)

Zileuton, a 5-lipoxygenase inhibitor, was evaluated as an inhibitor of cytochrome P450 activity in human liver microsomes. In the absence of preincubation, the racemate was found to be a weak inhibitor (IC₅₀ > 100 µM) of phenacetin O-deethylation (POD) (CYP1A2), paclitaxel 6-hydroxylation (CYP2C8), diclofenac 4'-hydroxylation (CYP2C9), (S)-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), testosterone 6ß-hydroxylation (CYP3A4), chlorzoxazone 6-hydroxylation (CYP2E1), and bupropion hydroxylation (CYP2B6). When preincubated with NADPH-fortified human liver microsomes in the absence of substrate, zileuton (racemate) was shown to inhibit POD. The effect was NADPH-, time-, and concentration-dependent, and was characterized by a k_inact (maximal rate of enzyme inactivation) and apparent K_I(inhibitor concentration that supports half the maximal rate of inactivation) of 0.035 min^-1 and 117 µM, respectively (k_inact/K_Iratio of 0.0003 min^-1 µM^-1). Preincubation-dependent inhibition of POD activity was also observed with the individual (S)-(-)- and (R)-(+)-enantiomers of zileuton [(S)-(-)-zileuton; k_inact, 0.037 min^-1, K_I, 98.2 µM, k_inact/K_Iratio, 0.0004 min^-1 µM^-1; (R)-(+)-zileuton; k_inact, 0.012 min^-1, K_I, 66.6 µM, k_inact/K_Iratio, 0.0002 min^-1 µM^-1]. In addition, the inhibition of CYP1A2 was not reversed in the presence of reduced glutathione, catalase, and superoxide dismutase and was refractory to dialysis. Therefore, zileuton was characterized as a mechanism-based inhibitor of human liver microsomal CYP1A2. Mechanism-based inhibition of CYP1A2 may explain why zileuton decreases the oral clearance of antipyrine, propranolol, (R)-warfarin, and theophylline, at doses that have a minimal effect on the pharmacokinetics of (S)-warfarin, phenytoin, and terfenadine.

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