PHARMACOKINETIC STEREOSELECTIVITY OF TROGLITAZONE, AN ANTIDIABETIC AGENT, IN THE KK MOUSE

Troglitazone, an oral antidiabetic agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ ho mogenate and in vivo plasma disposition in the KK mouse, an animal mod el of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 degrees C, there was a fivefold to eightfold acceler ation of epimerization at the 5 position of the thiazolidine ring in K K mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there wa s an approximately 1.3-fold difference in the epimerization rates amon g stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epim erization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of e pimerization is thought to be due to the high degree of protein bindin g because of the relationship between the initial epimerization rate a nd the dilution ratio of the plasma. Although acceleration of epimeriz ation was also observed in the 20% homogenates of liver, kidney, and i ntestine of the KK mouse, the degree of stereoselectivity was lower th an in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2.5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. (C) 1997 by John Wiley & Sons, Ltd.