Blood-to-brain influx transport of nicotine at the rat blood–brain barrier: Involvement of a pyrilamine-sensitive organic cation transport process

Nicotine is the most potent neural pharmacological alkaloid in tobacco, and the modulation of nicotine concentration in the brain is important for smoking cessation therapy. The purpose of this study was to elucidate the net flux of nicotine transport across the blood–brain barrier (BBB) and the major contributor to nicotine transport in the BBB. The in vivo brain-to-blood clearance was determined by a combination of the rat brain efflux index method and a rat brain slice uptake study, and the blood-to-brain transport of nicotine was evaluated by in vivo vascular injection in rats and a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB13 cells) as an in vitro model of the rat BBB. The blood-to-brain nicotine influx clearance was obtained by integration plot analysis as 272 μL/(min g brain), and this value was twofold greater than the brain-to-blood efflux clearance (137 μL/(min g brain)). Thus, it is suggested that the net flux of nicotine transport across the BBB is dominated by blood-to-brain influx transport. In vivo blood-to-brain nicotine transport was inhibited by pyrilamine. [3H]Nicotine uptake by TR-BBB13 cells exhibited time-, temperature-, and concentration-dependence with a Km value of 92 μM. Pyrilamine competitively inhibited nicotine uptake by TR-BBB13 cells with a Ki value of 15 μM, whereas substrates and inhibitors of organic cation transporters had little effect. These results suggest that pyrilamine-sensitive organic cation transport process(es) mediate blood-to-brain influx transport of nicotine at the BBB, and this is expected to play an important role in regulating nicotine-induced neural responses.

► Nicotine is the most potent neural pharmacological alkaloid in tobacco.
► Nicotine transport across the BBB is dominated by influx transport.
► In vivo blood-to-brain nicotine transport was inhibited by pyrilamine.
► OCT inhibitors had little effect on nicotine uptake by an in vitro BBB cell line.
► Pyrilamine competitively inhibited nicotine uptake by an in vitro BBB model cell line.