Stereoselective disposition of naproxen glucuronide in the rat

The disposition of R- and S-naproxen glucuronides were investigated after intravenous administration (approximately 1.5 mg/kg) to normal male Sprague-Dawley rats and to rats pretreated with phenylmethylsulfonylfluoride, an inhibitor of esterases. The relative stability of the two glucuronides also was measured in vitro. Both diastereomers were hydrolyzed rapidly in vivo, liberating naproxen, but R-naproxen glucuronide was hydrolyzed faster than the corresponding S-diastereomer. This difference resulted in a larger plasma AUC(Nap):AUC(Nap-G) ratio for the R-glucuronide. There was, however, no marked difference in the apparent clearance of the R- and S-diastereomers. Administration of phenylmethylsulfonylfluoride had no significant effect on the disposition of the two diastereomers. In 0.15 M phosphate buffer (ph 7.4) at 37 degree C, the fastest degradation process for both diastereomers in vitro was acyl migration. Our results show that R-naproxen glucuronide is more labile than S-naproxen glucuronide in vivo and in vitro, and suggest that hydrolysis, rather than biliary excretion, is the major process leading to elimination of R-naproxen glucuronide in vivo in the rat. These results demonstrate that the rat may in certain situations be an inadequate model for studying the disposition of acyl glucuronides and that the metabolic disposition, and possibly toxicities, of diastereomeric metabolites of chiral drugs can be quite different even when the individual diastereomers have similar apparent clearances.