Gender-Related Differences in the Expression of Organic Cation Transporter 2 and its Role in Urinary Excretion of Metformin in Rats.

Organic cation transporter 2 (rOCT2) and multidrug and toxin extrusion protein 1 (rMATE1) are mainly expressed in rat renal proximal tubules and mediate urinary excretion of cationic drugs, such as metformin. Accumulated evidence indicated that renal rOCT2 expression in male rats is much higher than that of female rats. However, it is unclear whether the gender-related differences in rOCT2 expression between male and female rats can affect the urinary excretion of metformin. The aim of this study was to investigate the effect of gender on the pharmacokinetics of metformin and to clarify the effect of gender-related differences on renal rOCT2 expression and its role in urinary excretion of metformin. Renal rOCT2 levels, but not rOCT1 and rMATE1, were significantly lowered in female rats when compared to that of male rats (P < 0.01), while the pharmacokinetic parameters, i.e., AUC0→t, t 1/2, CL/F, and cumulative urinary excretion of metformin, did not show any significant differences between female and male rats following oral administration of metformin at l00 mg/kg (P > 0.05). However, when metformin was orally administered at the dose of 500 mg/kg, the cumulative urinary excretion and renal tissue-to-plasma concentration ratio of metformin in female rats (26,689 ± 1266 μg and 2.96 ± 0.47 mL/g, respectively) were markedly lowered compared to that of male rats (32,949 ± 1384 μg and 4.20 ± 0.31 mL/g, respectively), and the plasma concentration of metformin in female rats (55.9 ± 4.5 μg/mL) was significantly increased compared to that of male rats (43.5 ± 3.1 μg/mL) at 2 h after oral administration. These results indicated that effect of gender-related differences on renal rOCT2 expression indeed contributes to the decreased urinary excretion of metformin in female rats when metformin was administered at relatively high doses.