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Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption.
Mol Pharm. 2010 Feb 01; 7(1):187-95.MP

Abstract

Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium using human bronchial epithelial BEAS-2B cells. [3H]Ipratropium uptake by BEAS-2B cells was temperature-dependent and saturable, with a K(m) value of 78.0 microM, suggesting involvement of carrier-mediated uptake. An RT-PCR study showed that organic cation/carnitine transporters OCTN1 and OCTN2 are expressed in BEAS-2B cells, but organic cation transporters (OCTs) are not. Uptake of [3H]ipratropium by HEK293 cells expressing OCTN1 (HEK293/OCTN1) and OCTN2 (HEK293/OCTN2) was significantly increased, compared with mock-transfected cells, and the estimated K(m) values were 444 microM and 53.0 microM, respectively. Finally, the contributions of OCTN1 and OCTN2 to ipratropium uptake were evaluated by measuring [3H]ipratropium uptake by BEAS-2B cells in which OCTN1 or OCTN2 gene expression had been silenced. Knock-down of OCTN1 or OCTN2 suppressed the uptake of [3H]ipratropium to 78.2% and 14.8% of that by control BEAS-2B cells, respectively. In addition, another anticholinergic, tiotropium, was also taken up by both HEK293/OCTN1 and HEK293/OCTN2 cells. Therefore, ipratropium and tiotropium are taken up primarily by OCTN2, and to a lesser extent by OCTN1, in bronchial epithelial cells. These findings are consistent with the pharmacological activity of the drugs after administration via inhalation.

Authors+Show Affiliations

Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20020740

Citation

Nakamura, Toshimichi, et al. "Transport of Ipratropium, an Anti-chronic Obstructive Pulmonary Disease Drug, Is Mediated By Organic Cation/carnitine Transporters in Human Bronchial Epithelial Cells: Implications for Carrier-mediated Pulmonary Absorption." Molecular Pharmaceutics, vol. 7, no. 1, 2010, pp. 187-95.
Nakamura T, Nakanishi T, Haruta T, et al. Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010;7(1):187-95.
Nakamura, T., Nakanishi, T., Haruta, T., Shirasaka, Y., Keogh, J. P., & Tamai, I. (2010). Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Molecular Pharmaceutics, 7(1), 187-95. https://doi.org/10.1021/mp900206j
Nakamura T, et al. Transport of Ipratropium, an Anti-chronic Obstructive Pulmonary Disease Drug, Is Mediated By Organic Cation/carnitine Transporters in Human Bronchial Epithelial Cells: Implications for Carrier-mediated Pulmonary Absorption. Mol Pharm. 2010 Feb 1;7(1):187-95. PubMed PMID: 20020740.
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TY - JOUR T1 - Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. AU - Nakamura,Toshimichi, AU - Nakanishi,Takeo, AU - Haruta,Tsunemitsu, AU - Shirasaka,Yoshiyuki, AU - Keogh,John P, AU - Tamai,Ikumi, PY - 2009/12/22/entrez PY - 2009/12/22/pubmed PY - 2010/4/20/medline SP - 187 EP - 95 JF - Molecular pharmaceutics JO - Mol Pharm VL - 7 IS - 1 N2 - Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium using human bronchial epithelial BEAS-2B cells. [3H]Ipratropium uptake by BEAS-2B cells was temperature-dependent and saturable, with a K(m) value of 78.0 microM, suggesting involvement of carrier-mediated uptake. An RT-PCR study showed that organic cation/carnitine transporters OCTN1 and OCTN2 are expressed in BEAS-2B cells, but organic cation transporters (OCTs) are not. Uptake of [3H]ipratropium by HEK293 cells expressing OCTN1 (HEK293/OCTN1) and OCTN2 (HEK293/OCTN2) was significantly increased, compared with mock-transfected cells, and the estimated K(m) values were 444 microM and 53.0 microM, respectively. Finally, the contributions of OCTN1 and OCTN2 to ipratropium uptake were evaluated by measuring [3H]ipratropium uptake by BEAS-2B cells in which OCTN1 or OCTN2 gene expression had been silenced. Knock-down of OCTN1 or OCTN2 suppressed the uptake of [3H]ipratropium to 78.2% and 14.8% of that by control BEAS-2B cells, respectively. In addition, another anticholinergic, tiotropium, was also taken up by both HEK293/OCTN1 and HEK293/OCTN2 cells. Therefore, ipratropium and tiotropium are taken up primarily by OCTN2, and to a lesser extent by OCTN1, in bronchial epithelial cells. These findings are consistent with the pharmacological activity of the drugs after administration via inhalation. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/20020740/Transport_of_ipratropium_an_anti_chronic_obstructive_pulmonary_disease_drug_is_mediated_by_organic_cation/carnitine_transporters_in_human_bronchial_epithelial_cells:_implications_for_carrier_mediated_pulmonary_absorption_ L2 - https://doi.org/10.1021/mp900206j DB - PRIME DP - Unbound Medicine ER -