STEREOSELECTIVE GLUCURONIDATION OF ZILEUTON ISOMERS BY HUMAN HEPATIC MICROSOMES

The glucuronidation of the R-isomer and S-isomer of the 5-lipoxygenase inhibitor zileuton was examined using human hepatic microsomes. The g lucuronidation of both isomers followed Michaelis-Menten kinetics, but glucuronidation rates were between 3.6- and 4.3-fold greater for the S-isomer. The apparent K-m's (mu M) for the R-isomer (392.9 +/- 35.9) and S-isomer (322.5 +/- 22.0) glucuronidation were similar, whereas th e apparent V-max (nmol/mg protein/min) was 3.4-fold greater for the S- isomer (5.2 +/- 0.7). In combination, each isomer competitively inhibi ted the glucuronidation of its antipode. The average K-i (mu M) determ ined for S-isomer inhibition of R-isomer glucuronidation (197.8 +/- 61 .3) was 2.4-fold lower than the K-i for the reciprocal interaction. Th ese data indicate that the gluouronidation of the zileuton isomers in human hepatic microsomes is stereoselective. This stereoselective gluc uronidation may be the basis for the more rapid clearance of the S-iso mer observed in humans receiving zileuton.