Stereoselective acyl glucuronidation and glucosidation of pranoprofen, a 2-arylpropionic acid derivative, in mice in vivo

Abstract

Following the oral administration of RS(+/-)-pranoprofen to mice at a dose of 25 mg/kg, 10.7% of the acyl glucuronide and 46.4% of the acyl glucoside of pranoprofen were excreted in the urine within 24 h. The recovery of acyl glucoside in the urine decreased relative to that of acyl glucuronide at increasing doses (100, 200 mg/kg). Following the oral administration of S(+)-pranoprofen to mice at a dose of 25 mg/kg, 5.0% of the acyl glucuronide and 56.5% of the acyl glucoside were excreted in the urine within 24 h, while 10.8% of the acyl glucuronide and 13.9% of the acyl glucoside were excreted after the oral administration of R(-)-pranoprofen, respectively. The absolute configuration of the aglycone of acyl glucuronide was almost R(-)-enantiomer (92.5-96.1%) in the 0-24 h urine, whereas that of acyl glucoside contained 15.3-24.7% of S(+)-enantiomer after the oral administration of R(-)-pranoprofen. On the other hand, only the S(+)-isomer was found as the aglycone of both acyl glucuronide and glucoside after the oral administration of S(+)-pranoprofen. The present results showed that stereoselective conjugation was observed in glucosidation in mice. Nevertheless, a dose-dependent shift in glucuronidation and glucosidation was found for both the administrations of S(+)- and R(-)-enantiomers as well as RS(+/-)-pranoprofen. Also a chiral inversion of R(-)-enantiomer to S(+)-antipode may occur slightly but significantly in mice.