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 pati...

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Veröffentlicht in:Journal of pharmaceutical and biomedical analysis 2022-04, Vol.212, p.114666-114666, Article 114666
Hauptverfasser: Saad, Abdulaziz Ahmed A., Zhang, Fan, Refat, Moath, Mohammed, Eyad Abdulwhab H., Zhang, Mingkang, Chen, Yuyue, Al Hamyari, Bandar, Alafifi, Jameel, Wu, Xin’an
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •This study reports a significant effect of tamsulosin on the pharmacokinetics of metformin in rats.•Tamsulosin significantly increases systemic exposure and reduces the excretion of metformin via inhibition of Mate1 and Oct2.•Remarkably increase the serum lactic acid (LCA) level in these two drugs co-administration after multiple doses.
ISSN:0731-7085
1873-264X
DOI:10.1016/j.jpba.2022.114666