Abstract
Ipratropium bromide (ipratropium) and tiotropium bromide (tiotropium) are anticholinergic agents with bronchodilating properties, used to treat patients with chronic obstructive pulmonary disease (COPD). Since they are actively secreted into urine, their interaction with organic cation transporters (OCTs/Octs) was examined in rat kidney slices and in cultured cells expressing rat (rOct) or human (hOCT) transporter. Uptake of radiolabeled ipratropium in rat kidney slices was significantly inhibited by OCT/Oct substrates, including cimetidine, imipramine and quinidine, but not by organic anion transporter substrates (e.g., p-aminohippuric acid, estrone-3-sulfate). [3H]Tiotropium uptake showed similar characteristics. RT-PCR showed that in rat kidney, mRNA expression of rOct2 was the highest, followed by rOct1, but little rOct3 was detected. In vitro, rOct1 and rOct2 transported both anticholinergics, but rOct3 accepted only ipratropium. Ipratropium uptake by rat kidney slices consisted of two components with Km values of 0.114 ± 0.06 µM and 24.5 ± 2.21 µM. The Km value of rOct2-mediated ipratropium uptake (0.143 ± 0.03 µM) was consistent with that of the high-affinity component. The OCT/Oct inhibitor corticosterone, at a concentration of 1 µM (IC50 1.11 ± 0.20 µM for rOct2-mediated ipratropium transport), inhibited ipratropium by 18.4%, suggesting that rOct2 is involved in renal secretion of ipratropium. Similarly, ipratropium and tiotropium were taken up by cultured cells expressing hOCT1 and hOCT2, but not hOCT3. We conclude that OCT2/Oct2 plays a role in renal secretion of both anticholinergics in these species. Co-administration of these anticholinergics with cationic drugs recognized by OCT2/Oct2 may decrease renal clearance, resulting in increased systemic exposure.
- Received July 12, 2010.
- Accepted October 20, 2010.
- The American Society for Pharmacology and Experimental Therapeutics