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Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats, a model for type 2 diabetes mellitus
Author(s) -
Tamura Masafumi,
Shiba Sachiko,
Kudo Naomi,
Kawashima Yoichi
Publication year - 2010
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20711
Subject(s) - chemistry , nateglinide , enantiomer , type 2 diabetes mellitus , diabetes mellitus , pharmacology , pharmacokinetics , metabolite , stereochemistry , type 2 diabetes , endocrinology , biochemistry , medicine
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 μmol/kg body weight. Nateglinide, its L‐enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CL tot ) 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, CL tot 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. CL tot 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 CL tot and V d compared with nateglinide, especially in the diabetic state. Chirality, 2010. © 2009 Wiley‐Liss, Inc.