Role of organic cation transporters in dopamine uptake across olfactory and nasal respiratory tissues.
Dopamine has poor oral bioavailability and low permeability across the blood-brain barrier, and yet it has been reported to have good systemic and central nervous system (CNS) bioavailability following nasal administration. The aim of this study was to investigate the extent to which dopamine transport in the olfactory and respiratory mucosae results from the activity of organic cation transporters (OCTs) present in the nasal cavity. Transport studies were carried out to determine the mechanism of dopamine transport across bovine olfactory and nasal respiratory mucosa. Western blotting and immunohistochemistry were performed to determine the expression and localization of organic cation transporter-2, a major transporter of dopamine, in the nasal mucosa. Dopamine transport was found to be saturable across both tissues. Amantadine, an organic cation transporter-1 (OCT-1) and organic cation transporter-2 (OCT-2) mixed inhibitor, decreased dopamine flux to a greater extent than guanidine, a more specific organic cation transporter-2 inhibitor. Immunohistochemistry results showed that organic cation transporter-2 was localized in both the epithelial and submucosal regions of the nasal olfactory and respiratory mucosa. Dopamine transport across the olfactory and respiratory mucosae is partially mediated by organic cation transporters, including OCT-1 and OCT-2. Utilization of uptake transporters may provide the opportunity for improved systemic absorption and targeted CNS delivery of dopamine and other drug compounds following nasal administration.
Chemuturi
Nagendra V
NV
Division of Pharmaceutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
Donovan
Maureen D
MD
D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D002417:Cattle; D004298:Dopamine / Q000493:pharmacokinetics*; D009297:Nasal Mucosa / Q000378:metabolism; D009831:Olfactory Mucosa / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism
D027701:Organic Cation Transport Proteins; D004298:Dopamine