Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.
Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular Kpof metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd.
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.
Yan-Rong
YR
Ma
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.|School of Pharmacy, Lanzhou University, Lanzhou, China.
A-Xi
AX
Shi
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.
Hong-Yan
HY
Qin
Department of Molecule Biosciences, Lincoln University, Canterbury, New Zealand.
Tiffany
T
Zhang
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.|School of Pharmacy, Lanzhou University, Lanzhou, China.
Yan-Fang
YF
Wu
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.
Guo-Qiang
GQ
Zhang
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, China.
Xin-An
XA
Wu
D058671:Adrenergic beta-1 Receptor Antagonists / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions / Q000502:physiology; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000097:blood* / Q000494:pharmacology; D008790:Metoprolol / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D058671:Adrenergic beta-1 Receptor Antagonists; D007004:Hypoglycemic Agents; D008687:Metformin; D008790:Metoprolol
drug interaction; metformin; metoprolol; pharmacokinetics; transporters