title: Influence of experimental diabetes and insulin treatment on the enantioselective pharmacokinetics of mexiletine and its metabolites.
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.
authors.affiliation: a Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida Café s/n Monte Alegre, Ribeirão Preto - CEP 14040-903, SP, Brazil.
authors.forename: Ana Leonor
authors.initials: AL
authors.lastname: Pardo Campos Godoy
authors.forename: Edson Z
authors.initials: EZ
authors.lastname: Martinez
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Andréia
authors.initials: A
authors.lastname: de Carvalho Leone
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barbosa Coelho
authors.forename: Vera
authors.initials: V
authors.lastname: Lucia Lanchote
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008297:Male; D008801:Mexiletine / Q000737:chemistry / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D007328:Insulin; D008801:Mexiletine