Received for publication December 6, 2004.
Revised March 14, 2005.
Accepted for publication March 14, 2005.

Acyl glucuronidation of fluoroquinolone antibiotics by the UDP-glucuronosyltransferase 1A subfamily in human liver microsomes

Abstract

Acyl glucuronidation is an important metabolic pathway for fluoroquinolone antibiotics. However, it is unclear which human UDP-glucuronosyltransferase (UGT) isoforms 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 as well as in cDNA-expressed recombinant human UGT isoforms. The apparent K_m values for human liver microsomes ranged 1.9-10 mM, and the intrinsic clearance values (calculated as V_max/K_m) were rank order of MFLX > STFX > GPFX >> LVFX. In a bank of human liver microsomes (n = 14), the glucuronidation activities of LVFX, MFLX, and STFX correlated highly with UGT1A1-selective -estradiol 3-glucuronidation activity, whereas GPFX glucuronidation activity correlated highly with UGT1A9-selective propofol glucuronidation activity. Among 12 recombinant human 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 the UGT1A1 most efficiently glucuronidates MFLX, whereas 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 IC₅₀ value of 9.8 µM. These results demonstrated that UGT1A1, 1A3, and 1A9 isoforms are involved in the acyl 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.

Key words: antibiotics, enzyme kinetics, glucuronidation, microsomes, phase II drug metabolism, UDP glucuronyltransferases

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