Pharmacokinetics of Nateglinide Enantiomers and Their Metabolites in Goto-Kakizaki Rats, a Model for Type 2 Diabetes Mellitus

The pharmacokinetics of (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) and its enantiomer (L-enantiomer) was studied in Goto-Kakizaki (GK) rats after intravenous administration of nateglinide or L-enantiomer at a dose of 40 mu mol/kg body weight. Nateglinide, its L-enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CLtot) and the volume of distribution (V-d) was slightly higher for nateglinide than those for L-enantiomer in control rats, although the differences were not: statistically significant. The cumulative excretions of L-M1 (major metabolite of L-enantiomer) and L-M2 (major metabolite of L-enantiomer) into bile were almost the same as that of M1 (major metabolite of nateglinide)and M2 (major metabolite of nateglinide). In GK rats, CLtot and V-d were higher for nateglinide than those for L-enantiomer. The cumulative excretion of L-M1 and L-M2 were not different from those of M1 and M2, respectively, into bile or urine. CLtot and V-d for nateglinide or L-enantiomer in GK rats were not different from those in control rats. The total excretion of M1, M2, L-M1, and L-M2 into bile or urine in GK rats was not substantially different from that of control rats. These results suggest that the L-enantiomer of nateglinide shows higher CLtot and V-d compared with nateglinide, especially in the diabetic state. Chirality 22:92-98, 2010. (C) 2009 Wiley-liss, Inc.