Sweeny D J, Nellans H N
Department of General Pharmacology, Abbott Laboratories, Abbott Park, IL 60064-3500.
Drug Metab Dispos. 1995 Jan;23(1):149-53.
The glucuronidation of the R-isomer and S-isomer of the 5-lipoxygenase inhibitor zileuton was examined using human hepatic microsomes. The glucuronidation 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 Km's (microM) for the R-isomer (392.9 +/- 35.9) and S-isomer (322.5 +/- 22.0) glucuronidation were similar, whereas the apparent Vmax (nmol/mg protein/min) was 3.4-fold greater for the S-isomer (5.2 +/- 0.7). In combination, each isomer competitively inhibited the glucuronidation of its antipode. The average Ki (microM) determined for S-isomer inhibition of R-isomer glucuronidation (197.8 +/- 61.3) was 2.4-fold lower than the Ki for the reciprocal interaction. These data indicate that the glucuronidation of the zileuton isomers in human hepatic microsomes is stereoselective. This stereoselective glucuronidation may be the basis for the more rapid clearance of the S-isomer observed in humans receiving zileuton.
利用人肝微粒体研究了5-脂氧合酶抑制剂齐留通的R-异构体和S-异构体的葡萄糖醛酸化反应。两种异构体的葡萄糖醛酸化反应均符合米氏动力学，但S-异构体的葡萄糖醛酸化速率比R-异构体高3.6至4.3倍。R-异构体（392.9±35.9）和S-异构体（322.5±22.0）葡萄糖醛酸化反应的表观Km（μM）相似，而S-异构体（5.2±0.7）的表观Vmax（nmol/mg蛋白/分钟）比R-异构体高3.4倍。两种异构体联合时，各自竞争性抑制其对映体的葡萄糖醛酸化反应。S-异构体抑制R-异构体葡萄糖醛酸化反应所测定的平均Ki（μM）（197.8±61.3）比其反向相互作用的Ki低2.4倍。这些数据表明，人肝微粒体中齐留通异构体的葡萄糖醛酸化反应具有立体选择性。这种立体选择性葡萄糖醛酸化反应可能是服用齐留通的人体内S-异构体清除更快的原因。
