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- Title
Influence of experimental diabetes and insulin treatment on the enantioselective pharmacokinetics of mexiletine and its metabolites.
- Authors
Pardo Campos Godoy, Ana Leonor; Martinez, Edson Z.; Marques, Maria Paula; de Carvalho Leone, Andréia; Barbosa Coelho, Eduardo; Lucia Lanchote, Vera
- Abstract
This study evaluates the influence of streptozotocin-induced diabetes on the kinetic disposition and metabolism of mexiletine (MEX) enantiomers in rats. Animals in the control ( n = 6 for each blood collection time), diabetic (single intravenous dosage of 45 mg·(kg body mass)−1 of streptozotocin), and insulin-treated groups (diabetic rats treated daily with 2 IU insulin) received by gavage a single dose of 10 mg·(kg body mass)−1 racemic MEX. MEX enantiomers and the metabolites hydroxymethylmexiletine (HMM) and p-hydroxymexiletine PHM) were analyzed by LC-MS/MS. Statistical analysis was based on a serial sacrifice design, and parameter estimation was performed using a Bayesian modeling procedure. Area under the curve (AUC) for the (−)-(R) enantiomers of MEX, HMM, and PHM did not differ between the control and diabetic groups. However, AUC for (+)-(S)-MEX and (+)-(S)-HMM were lower in the diabetic than in the control group. Insulin treatment recovered glucose levels to normal and the (+)-(S)-MEX AUC and (+)-(S)-HMM AUC became similar to the AUCs observed in the nondiabetic animals.
- Subjects
EXPERIMENTAL diabetes; INSULIN; ENANTIOSELECTIVE catalysis; PHARMACOKINETICS; MEXILETINE; METABOLITES; LABORATORY rats
- Publication
Canadian Journal of Physiology & Pharmacology, 2014, Vol 92, Issue 3, p263
- ISSN
0008-4212
- Publication type
Article
- DOI
10.1139/cjpp-2013-0218