The role of organic cation transporter 2 inhibitor cimetidine, experimentaldiabetes mellitusand metformin on gabapentin pharmacokinetics in rats

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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.


Glomerular filtration is the main mechanism of renal excretion of GAB without significant contribution of Oct2 active transport.

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