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Stereoselective glucuronidation of ofloxacin in rat liver microsomes

O Okazaki, T Kurata, H Hakusui and H Tachizawa

Drug Metabolism and Analytical Chemistry Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.

The stereoselective glucuronidation of ofloxacin [(+/-)-OFLX], a new quinolone antibacterial agent, was studied in vitro using rat liver microsomes. OFLX glucuronidation exhibited Michaelis-Menten kinetics in rat liver microsomes. Stereoselective glucuronidation of the optical enantiomers occurred. S-(-)-OFLX glucuronide was produced 7-fold more than R-(+)-OFLX glucuronide with little or no difference in the values of KM of the enantiomers. The value of Vmax/KM for the glucuronide conjugate of S-(-)-OFLX was 8-fold greater than for the conjugate of R- (+)-OFLX. These results demonstrate that OFLX undergoes stereoselective glucuronidation in vitro. Moreover, we studied the in vivo interaction between enantiomers of OFLX in rats to clarify the effects of R-(+)- OFLX on the metabolism and disposition of S-(-)-OFLX. When the racemate [(+/-)-OFLX (20 mg/kg)] or single enantiomer [S-(-)-OFLX (10 mg/kg)] is administered iv to the rat, the serum concentrations of S-(-)-OFLX were higher after racemate administration than those after enantiomer administration, although the dose of S-(-)-OFLX was identical in both cases. These results indicate that R-(+)-OFLX may compete with S-(-)- OFLX in the in vivo glucuronidation. Furthermore, the results of the enantiomeric inhibition study showed that R-(+)-OFLX competitively inhibited S-(-)-OFLX glucuronidation in vitro with a Ki value of 2.92 mM.

Volume 19, Issue 2, pp. 376-380, 03/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics




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H. Sasabe, Y. Kato, A. Tsuji, and Y. Sugiyama
Stereoselective Hepatobiliary Transport of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in the Rat
J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 661 - 668.
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Copyright © 1991 by the American Society for Pharmacology and Experimental Therapeutics.