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In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice.
J Pharm Sci. 2013 Sep; 102(9):3373-81.JP

Abstract

Ipratropium bromide (IPR) is an anticholinergic used to treat chronic obstructive pulmonary disease (COPD), and is a substrate of organic cation transporters. The present study aimed to assess the contribution of organic cation transporters to tracheobronchial absorption of IPR in vivo by directly injecting [(3) H]IPR into the tracheal lumen of mice and measuring its accumulation in tracheal tissue. RT-PCR and immunohistochemical analysis showed that Octn1, Octn2, and Oct2 were localized at epithelial cells in the respiratory tract. Electron-microscopic immunohistochemistry indicated that Octn1 and Octn2 were localized at the apical portions of ciliated epithelial cells of trachea. In vitro uptake studies in HEK293 cells expressing these transporters demonstrated that IPR is a preferred substrate of Octn2. Inhibition of mouse tracheal accumulation of [(3) H]IPR by carnitine was concentration-dependent, reaching a maximum of 42% at 1 mM, whereas inhibition by 0.1 mM MPP(+) amounted to 62%. Tracheal accumulation of [(3) H]IPR was unchanged when mice were simultaneously injected with Octn1 substrate ergothioneine and organic anion transporter substrate estrone sulfate. These results suggest that Octn2 is involved in membrane permeation of IPR in the respiratory tract in vivo. Targeting organic cation transporters may be an effective strategy for delivery of cationic anti-COPD drugs to patients.

Authors+Show Affiliations

Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23686692

Citation

Nakanishi, Takeo, et al. "In Vivo Evidence of Organic Cation Transporter-mediated Tracheal Accumulation of the Anticholinergic Agent Ipratropium in Mice." Journal of Pharmaceutical Sciences, vol. 102, no. 9, 2013, pp. 3373-81.
Nakanishi T, Hasegawa Y, Haruta T, et al. In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice. J Pharm Sci. 2013;102(9):3373-81.
Nakanishi, T., Hasegawa, Y., Haruta, T., Wakayama, T., & Tamai, I. (2013). In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice. Journal of Pharmaceutical Sciences, 102(9), 3373-81. https://doi.org/10.1002/jps.23603
Nakanishi T, et al. In Vivo Evidence of Organic Cation Transporter-mediated Tracheal Accumulation of the Anticholinergic Agent Ipratropium in Mice. J Pharm Sci. 2013;102(9):3373-81. PubMed PMID: 23686692.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice. AU - Nakanishi,Takeo, AU - Hasegawa,Yoshitaka, AU - Haruta,Tsunemitsu, AU - Wakayama,Tomohiko, AU - Tamai,Ikumi, Y1 - 2013/05/19/ PY - 2013/03/25/received PY - 2013/04/12/revised PY - 2013/04/16/accepted PY - 2013/5/21/entrez PY - 2013/5/21/pubmed PY - 2014/3/7/medline KW - COPD KW - OCT KW - OCTN KW - epithelial KW - membrane transport/transporters KW - permeability KW - pulmonary delivery/absorption SP - 3373 EP - 81 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 102 IS - 9 N2 - Ipratropium bromide (IPR) is an anticholinergic used to treat chronic obstructive pulmonary disease (COPD), and is a substrate of organic cation transporters. The present study aimed to assess the contribution of organic cation transporters to tracheobronchial absorption of IPR in vivo by directly injecting [(3) H]IPR into the tracheal lumen of mice and measuring its accumulation in tracheal tissue. RT-PCR and immunohistochemical analysis showed that Octn1, Octn2, and Oct2 were localized at epithelial cells in the respiratory tract. Electron-microscopic immunohistochemistry indicated that Octn1 and Octn2 were localized at the apical portions of ciliated epithelial cells of trachea. In vitro uptake studies in HEK293 cells expressing these transporters demonstrated that IPR is a preferred substrate of Octn2. Inhibition of mouse tracheal accumulation of [(3) H]IPR by carnitine was concentration-dependent, reaching a maximum of 42% at 1 mM, whereas inhibition by 0.1 mM MPP(+) amounted to 62%. Tracheal accumulation of [(3) H]IPR was unchanged when mice were simultaneously injected with Octn1 substrate ergothioneine and organic anion transporter substrate estrone sulfate. These results suggest that Octn2 is involved in membrane permeation of IPR in the respiratory tract in vivo. Targeting organic cation transporters may be an effective strategy for delivery of cationic anti-COPD drugs to patients. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/23686692/In_vivo_evidence_of_organic_cation_transporter_mediated_tracheal_accumulation_of_the_anticholinergic_agent_ipratropium_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)30950-3 DB - PRIME DP - Unbound Medicine ER -