Kinetic analysis of tolbutamide-sulfonamide interaction in rabbits based on clearance concept. Prediction of species difference from in vitro plasma protein binding and metabolism

Abstract

The interaction between tolbutamide (TB) and sulfonamide (SA) in rabbits was quantitatively investigated by both in vivo and in vitro experiments, and the mechanisms of species difference between rabbits and rats were analyzed by comparing the two total body clearances (CLtot) obtained from in vivo and in vitro studies. The sulfonamides used were sulfaphenazole (SP) and sulfadimethoxine (SDM). In vivo CLtot of TB was changed little by SA in rabbits, which was contrary to the phenomenon seen in rats, i.e. CLtot was markedly decreased by SA in rats (Sugita et al., Biochem. Pharmacol., 30, 3347, 1981). The total body clearance defined as CL in vitro tot.pred was predicted for TB in the presence and absence of SA by the equation: CL in vitro tot.pred congruent to fB CL in vitro int, where fB is the blood-free fraction and CL in vitro int is the hepatic intrinsic clearance of unbound drug obtained from in vitro experiments using liver microsomal fraction. A comparatively good agreement was observed between the two CLtot obtained from in vivo and in vitro data. The analysis in rabbits based on these in vitro experiments showed that the small gross changes of in vivo CLtot induced by SA were due to the compensative changes of two factors, i.e. fB and CL in vitro int which in the presence of SA were approximately 200 and 50% of the control, respectively. However, in rats, the marked decrease of in vivo CLtot induced by SA was explained by the greater degree of the decrease in CL in vitro int than that of the increase in fB.(ABSTRACT TRUNCATED AT 250 WORDS)