Clinical Aspects of Drug-Drug Interaction and Drug Nephrotoxicity at Renal Organic Cation Transporters 2 (OCT2) and Multidrug and Toxin Exclusion 1, and 2-K (MATE1/MATE2-K).

The organic cation transporter 2 (OCT2) belongs to the SLC22 family, while the multidrug and toxin extrusion 1 and 2-K (MATE1/MATE2-K) belong to the SLC47 family, are localized to the basolateral and apical membrane of human renal proximal tubular epithelial cells, respectively. They are polyspecific transporters that enable the transit of structurally diversified drugs with overlapping selectivity across plasma membranes. OCT2 and MATE1/2-K are critically involved in renal secretion, pharmacokinetics (PK), and toxicity of cationic drugs. Drug-drug interactions (DDIs) at OCT2 and/or MATE1/2-K have been shown to result in clinical impacts on PK, therapeutic efficacy and are probably involved in the renal accumulation of drugs. Sites of OCT2 and MATE1/2-K expression and function play an essential role in the pharmacokinetics and toxicity of drugs, such as cisplatin. Thus, knowing the sites (basolateral vs. apical) of the interaction of two drugs at transporters is essential to understanding whether this interaction helps prevent or enhance drug-induced nephrotoxicity. In this work, an overview of OCT2 and MATE1/2-K is presented. Primary structure, membrane location, functional properties, and clinical impact of OCT2 and MATE1/2-K are presented. In addition, clinical aspects of DDIs in OCT2 and MATE1/2-K and their involvement in drug nephrotoxicity are compiled.

Tamsulosin alters the pharmacokinetics of metformin via inhibition of renal multidrug and toxin extrusion protein 1 and organic cation transporter 2 in rats.

Among the endocrine and metabolic disorders, type-2 diabetes mellitus (T2DM) and benign prostatic hyperplasia (BPH) are common progressive diseases related to aging. Metformin and tamsulosin as the first-choice drug for patients with T2DM and BPH, respectively, are often co-administered to male patients with T2DM and BPH. However, whether concomitantly administering metformin and tamsulosin leads to drug-drug interactions (DDIs) remains unclear. This study aimed to evaluate the effect of tamsulosin on the pharmacokinetics of metformin and explore the relevant underlying mechanism. The plasma, urine, and tissue concentrations of metformin were analyzed using HPLC, and metformin cell uptake was analyzed using LC-MS/MS. In addition, western blotting was used to investigate the expression of Oct1, Oct2, and Mate1. As demonstrated by comparison with metformin alone, tamsulosin significantly increased the area under concentration-time curves (AUC0-t), the maximum plasma concentration (Cmax) and the decreased 24 h cumulative urinary excretion of metformin after single or multiple-dose administration in rats, as well as increased the kidney tissue concentration of metformin after multiple-dose. In addition, tamsulosin treatment significantly inhibited the expression of Mate1 and Oct2 in rat kidneys, but Oct1 and Mate1 did not show a significant difference in the liver. Consistently, tamsulosin inhibited OCT2 and MATE1 expressions and decreased metformin uptake in HEK293 cells. Notably, serum LCA level in the co-administration group was increased by 34% and 39% after multiple-dose (7 and 14 consecutive days, respectively) administration compared to the metformin alone group. Altogether, our data suggest that tamsulosin could increase systemic exposure and reduce excretion of metformin via inhibiting Oct2 and Mate1-mediated transport cooperatively.