Influence of the organic cation transporter 2 (OCT2) inhibitor cimetidine and experimental diabetes mellitus on kinetic disposition of gabapentin in rats

Abstract

The organic cation transporter 2 (OCT2), expressed at the basolateral membrane of proximal tubule of the kidneys, plays an important role in the elimination of several clinically available drugs. Gabapentin (GBP), anticonvulsant used to treat neuropathic pain, is partially eliminated by renal active secretion via OCT2. The experimental diabetes mellitus (EDM) induced by streptozotocin (STZ) reduces OCT2 activity by 50-70% in rats. The objective of this study is to investigate the influence of EDM, glycemic control and the OCT2 inhibitor cimetidine on the kinetic disposition of GBP in rats. Male Wistar rats will be divided into four groups: control, cimetidine (single dose of 100 mg/kg, i.p. cimetidine), diabetic (single dose of 45 mg/kg i.v. STZ) and insulin treated diabetic (single dose of 45 mg/kg i.v.STZ and 4 U/day insulin subcutaneously, 14 days). Animals (n=6 per sampling time) will be treated with a single dose of 50 mg/kg GBP p.o. (gavage) and blood samples will be collected at 15, 30 and 45 min, 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours and the urine will be collected at 0-12h after administration. GBP plasma concentrations will be analysed by liquid chromatography coupled to mass spectrometry (LC-MS). The area under the plasma concentration × time curve (AUC) will be calculated from time zero to infinity based on the Gauss-Laguerre Quadrature. The apparent total clearance (CL/F) will be calculated by the equation: CL/F = dose/AUC0-. The pharmacokinetic parameters will be compared between groups by 95% confidence intervals. Based on the results, it will be possible evaluate the influence of EDM and its glycemic control on the kinetic disposition of GBP, as well as to evaluate the relevance of OCT2 activity using the inhibitor cimetidine in the renal excretion of the drug. (AU)