title: Inhibitory effect of atenolol on urinary excretion of metformin via down-regulating multidrug and toxin extrusion protein 1 (rMate1) expression in the kidney of rats.
abstract: Renal tubular secretion is an important pathway for the elimination of many clinically used drugs. Metformin, a commonly prescribed first-line antidiabetic drug, is secreted primarily by the renal tubule. Many patients with type 2 diabetes mellitus (T2DM) receiving metformin may together be given selective β1 blockers (e.g., atenolol). Therefore, it is of great use to evaluate the effect of atenolol on metformin urinary excretion for exploring drug interactions and predicting the adverse effect of drugs. The aim of this study was to investigate the effect of atenolol on the pharmacokinetic of metformin and plasma lactate (LCA) level in rats, for high LCA is a serious adverse reaction of metformin after long-term metformin treatment. In this study, rats were treated with metformin alone or in combination with atenolol. Plasma, urine and tissue concentration of metformin was determined by HPLC method, while Western blotting and immunohistochemical analysis were used to evaluate the renal expression of rat organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1). The results showed that, after 7 days drug treatment, the AUC0 → t of metformin in atenolol and metformin co-administration group was significantly increased by 19.5% compared to that in metformin group, while the 24h cumulative urinary excretion of metformin was significantly decreased by 57.3%. In addition, atenolol treatment significantly decreased the renal expression of rMate1, but had no effect on rOct2 expression, renal blood perfusion and glomerular filtration. Moreover, plasma LCA level in atenolol and metformin co-administration group was significantly increased by 83.3% compared to that in metformin group after 60 days drug treatment. These results indicated that atenolol can inhibit urinary excretion of metformin via decreasing renal rMate1 expression, and long-term atenolol and metformin co-administration may induce potential lactic acidosis. Our results, for the first time, provided an important experimental evidence that rMate1 is the target of transporter-mediated drug interactions concerning metformin and atenolol.
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yan-rong
authors.initials: YR
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yun-yun
authors.initials: YY
authors.lastname: Shao
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Guo-qiang
authors.initials: GQ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Rao
authors.initials: R
authors.lastname: Zhi
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
authors.forename: Hong-yan
authors.initials: HY
authors.lastname: Qin
authors.affiliation: Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China. Electronic address: xinanwu6511@163.com.
authors.forename: Xin-an
authors.initials: XA
authors.lastname: Wu
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001262:Atenolol / Q000494:pharmacology*; D015536:Down-Regulation; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D017920:Antiporters; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C100590:Slc22a2 protein, rat; C515734:Slc47a1 protein, rat; D001262:Atenolol; D008687:Metformin
keywords: Atenolol; Metformin; Urinary excretion; rMate1; rOct2