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ACYL GLUCURONIDATION OF FLUOROQUINOLONE ANTIBIOTICS BY THE UDP-GLUCURONOSYLTRANSFERASE 1A SUBFAMILY IN HUMAN LIVER MICROSOMES

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (M.Tac., Y.M., T.H.); and Drug Metabolism and Physicochemistry Research Laboratories, R&D Division, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan (M.Tac., M.Tan.)

Acyl glucuronidation is an important metabolic pathway for fluoroquinolone antibiotics. However, it is unclear which human UDP-glucuronosyltransferase (UGT) enzymes are involved in the glucuronidation of the fluoroquinolones. The in vitro formation of levofloxacin (LVFX), grepafloxacin (GPFX), moxifloxacin (MFLX), and sitafloxacin (STFX) glucuronides was investigated in human liver microsomes and cDNA-expressed recombinant human UGT enzymes. The apparent K_m values for human liver microsomes ranged from 1.9 to 10.0 mM, and the intrinsic clearance values (calculated as V_max/K_m) had a rank order of MFLX > GPFX > STFX >> LVFX. In a bank of human liver microsomes (n = 14), the glucuronidation activities of LVFX, MFLX, and STFX correlated highly with UGT1A1-selective ß-estradiol 3-glucuronidation activity, whereas the glucuronidation activity of GPFX correlated highly with UGT1A9-selective propofol glucuronidation activity. Among 12 recombinant UGT enzymes, UGT1A1, 1A3, 1A7, and 1A9 catalyzed the glucuronidation of these fluoroquinolones. Results of enzyme kinetics studies using the recombinant UGT enzymes indicated that UGT1A1 most efficiently glucuronidates MFLX, and UGT1A9 most efficiently glucuronidates GPFX. In addition, the glucuronidation activities of MFLX and STFX in human liver microsomes were potently inhibited by bilirubin with IC₅₀ values of 4.9 µM and 4.7 µM, respectively; in contrast, the glucuronidation activity of GPFX was inhibited by mefenamic acid with an IC₅₀ value of 9.8 µM. These results demonstrate that UGT1A1, 1A3, and 1A9 enzymes are involved in the glucuronidation of LVFX, GPFX, MFLX, and STFX in human liver microsomes, and that MFLX and STFX are predominantly glucuronidated by UGT1A1, whereas GPFX is mainly glucuronidated by UGT1A9.

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