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 50â¯mg/kg GAB: (vehicleâ¯+â¯GAB), cimetidineâ¯+â¯GAB (single dose of cimetidine [100â¯mg/kg] intraperitoneally 1â¯h before GAB), metforminâ¯+â¯GAB (single dose of metformin 100â¯mg/kg by gavage concomitantly with GAB), DMâ¯+â¯GAB (single dose of 40â¯mg/kg streptozotocin (STZ) intravenously) and DMâ¯+â¯GABâ¯+â¯insulin (single dose 40â¯mg/kg STZ intravenously and 2â¯IU insulin twice daily for 15â¯days). Pharmacokinetic analysis was based on plasma and urine data concentrations. KEY FINDINGS: No differences in pharmacokinetic parameters were observed between vehicleâ¯+â¯GABâ¯×â¯cimetidineâ¯+â¯GAB and vehicleâ¯+â¯GABâ¯×â¯metforminâ¯+â¯GAB groups. Diabetes increased the fraction of GAB excreted unchanged in urine (vehicleâ¯+â¯GAB: 0.48 [0.38-0.58]; DMâ¯+â¯GAB: 0.83 [0.62-1.04]; DMâ¯+â¯GABâ¯+â¯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 (vehicleâ¯+â¯GAB: 0.25 [0.18-0.30] L/h·kg; DMâ¯+â¯GABâ¯+â¯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.