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

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

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. Male Wistar rats were divided in five groups and all animals received an oral dose of 50 mg/kg GAB: (vehicle +...

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Bibliographic Details
Published in:Life sciences (1973) Vol. 200; pp. 63 - 68
Main Authors: Benzi, Jhohann Richard de Lima, Yamamoto, Priscila Akemi, Stevens, Jessica Hanna, Baviera, Amanda Martins, de Moraes, Natália Valadares
Format: Journal Article
Language:English
Published: Netherlands Elsevier Inc 01-05-2018
Elsevier BV
Subjects:
Active transport
Animals
Cimetidine
Confidence intervals
Diabetes
Diabetes mellitus
Excretion
Gabapentin
Hyperfiltration
Inhibitor drugs
Inhibitors
Insulin
Metformin
Oct-2 protein
Oct2
Organic cation transporter
Pharmacokinetics
Pharmacology
Rats
Renal function
Rodents
Streptozocin
Substrate inhibition
Urine
Gabapentin
Pharmacokinetics
Diabetes mellitus
Oct2
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Summary: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. 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. 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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ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2018.03.012