Role of age-related decrease of renal organic cation transporter 2 in the effect of atenolol on renal excretion of metformin in rats.

Abstract

Many diabetes patients, especially the elder ones, suffered from hypertension simultaneously. Therefore, it is very likely that a large number of diabetes patients receiving metformin hydrochloride may simultaneously be given beta-blockers. Knowing that both metformin and atenolol are eliminated by organic cation transporter 2 (OCT2/SLC22A2) expressed in the renal basolateral membrane, it is not clear whether there is a competitive effect on the renal excretion of metformin and/or atenolol when metformin and atenolol were co-administered, and whether age was involved in this drug-drug interaction. In this present study, both young rats (aged 3 months) and aged rats (aged 12 months) were used, rats were divided into metformin-treated group and metformin and atenolol co-administrated group, respectively. Either metformin (2.5 mg/kg) alone or metformin (2.5 mg/kg) in combination with atenolol (8 mg/kg) was administered to rats by tail vein injection. Then, urine was collected and the metformin concentration in urine was determined by HPLC. The localization and expression of rOCT2 in kidney were also investigated by Western blotting and immunohistochemistry. Significant differences of t 1/2, K e, CLtot and the accumulated metformin excretion in urine were founded in aged rats, but not in young rats, between metformin-treated group (2.002 ± 0.51 h, 0.346 ± 0.07/h, 57.161 ± 18.59 %, 4,287.087 ± 458.08 μg) and metformin plus atenolol-treated group (3.03 ± 0.67 h, 0.228 ± 0.05/h, 43.199 ± 10.28 %, 3,239.972 ± 446.61 μg). Moreover, a significant age-related decrease in rOCT2 protein expression was observed in the aged rats (P < 0.01), which may be responsible for the effect of atenolol on the renal excretion of metformin in the aged rats. In conclusion, there is a drug-drug interaction between atenolol and metformin, and more attention should be paid when atenolol and metformin were co-administered to the aged people inclinical.