The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

Abstract Purpose We investigated the influence of diabetes mellitus (DM), glycemic control with insulin, cimetidine (Oct2 inhibitor) and metformin (Oct2 substrate) on the kinetic disposition of GAB in rats. Main methods Male Wistar rats were divided in five groups and all animals received an oral dose of 50 mg/kg GAB: (vehicle + GAB), cimetidine + GAB (single dose of cimetidine [100 mg/kg] intraperitoneally 1 h before GAB), metformin + GAB (single dose of metformin 100 mg/kg by gavage concomitantly with GAB), DM + GAB (single dose of 40 mg/kg streptozotocin (STZ) intravenously) and DM + GAB + insulin (single dose 40 mg/kg STZ intravenously and 2 IU insulin twice daily for 15 days). Pharmacokinetic analysis was based on plasma and urine data concentrations. Key findings No differences in pharmacokinetic parameters were observed between vehicle + GAB × cimetidine + GAB and vehicle + GAB × metformin + GAB groups. Diabetes increased the fraction of GAB excreted unchanged in urine (vehicle + GAB: 0.48 [0.38–0.58]; DM + GAB: 0.83 [0.62–1.04]; DM + GAB + insulin: 0.88 [0.77–0.93]) (mean [95% confidence interval]) without any changes in GAB exposure. Insulin treated diabetic animals showed higher renal clearance compared to control (vehicle + GAB: 0.25 [0.18–0.30] L/h·kg; DM + GAB + insulin: 0.55 [0.45–1.43] L/h·kg), which was attributed to the diabetes-induced glomerular hyperfiltration. Significance Glomerular filtration is the main mechanism of renal excretion of GAB without significant contribution of Oct2 active transport.