Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells

• Published in: Journal of pharmaceutical sciences Vol. 106; no. 9; pp. 2576 - 2582
• Main Authors: Kurosawa, Toshiki, Higuchi, Kei, Okura, Takashi, Kobayashi, Kazumasa, Kusuhara, Hiroyuki, Deguchi, Yoshiharu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2017
• Subjects: Animals; Antiporters - chemistry; Antiporters - metabolism; basic drug; Biological Transport; blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Diphenhydramine - chemistry; Diphenhydramine - metabolism; Endothelial Cells - metabolism; Endothelium, Vascular - metabolism; Humans; Kinetics; Male; Nicotinic Agonists - administration & dosage; Nicotinic Agonists - chemistry; Nicotinic Agonists - metabolism; Organic Cation Transport Proteins - metabolism; organic cation transporter; Protons; Rats; Receptors, Nicotinic - metabolism; Thermodynamics; varenicline; Varenicline - administration & dosage; Varenicline - chemistry; Varenicline - metabolism; basic drug; blood-brain barrier; varenicline; organic cation transporter
• DOI: 10.1016/j.xphs.2017.04.032
• ISSN: 0022-3549; 1520-6017

Varenicline is a selective partial α4β2 nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H+/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H+/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H+/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.