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

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.

In vitro/in vivo characterization of melt-molded gabapentin-loaded poly(epsilon-caprolactone) implants for sustained release in animal studies.

Gabapentin (GBP) is a water soluble low molecular weight drug with anticonvulsivant and antinociceptive activity. In animal models, systemic administration regimes resembling chronic exposure to this drug (50mg/kg, twice a day during one week), induce memory impairment. Aiming to gain further insight on the mechanisms involved in this process, a monolithic implant that releases constant plasma levels during one-week was designed. GBP-loaded poly(epsilon-caprolactone) matrices were produced by means of a simple and reproducible melt-molding/compression procedure. In vitro release studies firstly comprised uncoated implants that displayed release profiles according to a pseudo-first order model. In order to further regulate the release, two-sided coated implants where drug-free layers would perform as membranes controlling the delivery rate were prepared. A more moderated burst effect and a relatively linear (zero-order) release between days 1 and 7 were apparent. Implants were investigated in vivo and the plasma levels monitored during 10 days. Findings indicated that after a more pronounced release during day 1 and the achievement of the levels in blood comparable to a twice-a-day intraperitoneal management, relatively constant levels were attained until day 7. Overall results support the usefulness of this manufacturing method for the production of implants to attain more prolonged GBP release profiles in memory animal studies.