氧氟沙星对映体在经不同诱导剂诱导的大鼠肝微粒体中的葡醛酸化代谢(英文)

Glucuronidation metabolism of ofloxacin enantiomers in rat microsomes treated with different inducers

为评价氧氟沙星 ( OFLX)对映体葡醛酸化代谢的立体选择性 ,采用手性 HPLC法测定大鼠肝微粒体孵育液中 OFLX对映体 .结果显示 :经苯巴比妥 ( PB)和β-萘黄酮 ( BNF)诱导的不同葡醛酸转移酶 ( UDPGT)亚族对 OFLX对映体葡醛酸化代谢有不同的影响 .在所试验的对照 ,PB或 BNF诱导的微粒体中 S- ( - ) -和 R- ( + ) - OFLX之间 ,Km 和Vmax无显著性差异 ;但 PB组中 S- ( - ) -和 R- ( + ) -OFLX的 Km 和 Vmax与对照组或 BNF组相应的对映体比较有显著性差异 ;OFLX对映体之间的 Clint在对照组与 BNF组没有显著性差异 ;而在 PB组则有显著性差异 .另外 BNF组的 Clint较对照组和 PB组分别有显著性差异 .因此 ,经 PB诱导的 UDPGT亚族对 S-和 R- OFLX的 相代谢存在立体选择性 ,并主要是由于其催化部位的差异引起了内在清除率的变化 .

To examine stereoselective metabolism of ofloxacin (OFLX) enantiomers in the glucuronidation process, enantiomers of OFLX in rat liver microsomal incubates were determined by chiral RP HPLC. The results indicated that there was no significant difference for K m and V max between enantiomers in control, phenobarbital(PB) or β naphthoflavone(BNF) induced microsomes, but there were the differences for corresponding enantiomers between PB group and control group or BNF group. Intrinsic clearance (Cl int ) of BNF group was increased significantly comparing with control group and PB group. Both Cl int values of S (-) and R (+) OFLX for the isozyme treated with BNF were higher than that treated with PB.The stereoselectivity was observed in PB group with Cl int of S (-) enantiomer higher than that of R (+) enantiomer. The differences occurred mainly at the catalytic site of isozyme and therefore cause variations in Cl int .