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Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans.
Drug Metab Dispos. 2011 Jan; 39(1):117-22.DM

Abstract

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). [(3)H]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 K(m) values of 0.114 ± 0.06 and 24.5 ± 2.21 μM. The K(m) 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 (IC(50), 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.

Authors+Show Affiliations

Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20962061

Citation

Nakanishi, Takeo, et al. "Organic Cation Transporter-mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 39, no. 1, 2011, pp. 117-22.
Nakanishi T, Haruta T, Shirasaka Y, et al. Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans. Drug Metab Dispos. 2011;39(1):117-22.
Nakanishi, T., Haruta, T., Shirasaka, Y., & Tamai, I. (2011). Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 39(1), 117-22. https://doi.org/10.1124/dmd.110.035402
Nakanishi T, et al. Organic Cation Transporter-mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans. Drug Metab Dispos. 2011;39(1):117-22. PubMed PMID: 20962061.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans. AU - Nakanishi,Takeo, AU - Haruta,Tsunemitsu, AU - Shirasaka,Yoshiyuki, AU - Tamai,Ikumi, Y1 - 2010/10/20/ PY - 2010/10/22/entrez PY - 2010/10/22/pubmed PY - 2011/7/6/medline SP - 117 EP - 22 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 39 IS - 1 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). [(3)H]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 K(m) values of 0.114 ± 0.06 and 24.5 ± 2.21 μM. The K(m) 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 (IC(50), 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/20962061/Organic_cation_transporter_mediated_renal_secretion_of_ipratropium_and_tiotropium_in_rats_and_humans_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20962061 DB - PRIME DP - Unbound Medicine ER -