TY - JOUR T1 - Organic Cation Transporter-Mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 117 LP - 122 DO - 10.1124/dmd.110.035402 VL - 39 IS - 1 AU - Takeo Nakanishi AU - Tsunemitsu Haruta AU - Yoshiyuki Shirasaka AU - Ikumi Tamai Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/39/1/117.abstract N2 - Ipratropium bromide (ipratropium) and tiotropium bromide (tiotropium), anticholinergic agents with bronchodilating properties, are used to treat patients with chronic obstructive pulmonary disease. Because they are actively secreted into urine, the interaction of these agents with organic cation transporters (OCTs/Octs) was examined in rat kidney slices and in cultured cells expressing rat Oct (rOct) or human OCT (hOCT). 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 and estrone-3-sulfate). [3H]Tiotropium uptake showed similar characteristics. Reverse transcription-polymerase chain reaction 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 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. In a similar manner, 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. Coadministration of these anticholinergics with cationic drugs recognized by OCT2/Oct2 may decrease renal clearance, resulting in increased systemic exposure. ER -