Clonidine Transport at the Mouse Blood—Brain Barrier by a New H⁺ Antiporter that Interacts with Addictive Drugs

Abstract

Identifying drug transporters and their in vivo significance will help to explain why some central nervous system (CNS) drugs cross the blood-brain barrier (BBB) and reach the brain parenchyma. We characterized the transport of the drug clonidine at the luminal BBB by in situ mouse brain perfusion. Clonidine influx was saturable, followed by Michaelis-Menten kinetics (K m = 0.62 mmol/L, V max = 1.76 nmol/sec per g at pH 7.40), and was insensitive to both sodium and trans-membrane potential. In vivo manipulation of intracellular and/or extracellular pH and trans-stimulation showed that clonidine was transported by an H + -coupled antiporter regulated by both proton and clonidine gradients, and that diphenhydramine was also a substrate. Organic cation transporters (Oct1-3), P-gp, and Bcrp did not alter clonidine transport at the BBB in knockout mice. Secondary or tertiary amine CNS compounds such as oxycodone, morphine, diacetylmorphine, methylenedioxyamphetamine (MDMA), cocaine, and nicotine inhibited clonidine transport. However, cationic compounds that interact with choline, Mate, Octn, and Pmat transporters did not. This suggests that clonidine is transported at the luminal mouse BBB by a new H + -coupled reversible antiporter.

Coexistence of Passive and Proton Antiporter-Mediated Processes in Nicotine Transport at the Mouse Blood–Brain Barrier

“…Our results suggest that the transport of nicotine across the mouse BBB involves a passive component and a distinct "proton/amine" antiporter that also transports tramadol and diphenhydramine (7). The features of this reversible "proton/ amine" antiporter at the mouse BBB highlight its importance in facilitating the rate and extent of the delivery of nicotine to the brain.…”

“…3b). The lack of sodium with or without chloride depletion in the vascular compartment, which is known to acidify the BBB (7,14), increased the brain transport of [ 3 H]-nicotine by 1.72-fold (p<0.01).…”

“…Nicotine inhibits/interacts with this transporter, as do some other psychotropic drugs like opiates (7). Earlier transport experiments using Caco-2 cells and slices of rat kidney have shown that the movement of nicotine is due to both passive and facilitated antiporter-mediated fluxes (8,9).…”

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

“…This process was found to be energy and pH dependent but independent of sodium and membrane potential. Evidence that these putative pyrilamine cationic transporters may participate in an antiporter system came when the transport of secondary or tertiary amine drugs (e.g., nicotine, 15 clonidine, 16 and tramadol 17 ), which shows similar characteristics as pyrilamine transport, was found to be driven by an adverse proton gradient. Pyrilamine inhibited the tranport process, suggesting the existence of a pyrilamine-senstive H + /OC-antiporter.…”

Characterization of an L-Carnitine Transport System in Murine Photoreceptor Cell Line

“…In addition, it has been reported that, although molecular entity remains unknown, clonidine uptake by mouse brain microvascular endothelial cells show a pHdependent profile, suggesting a potential involvement of H + antiport. 28) In other cases, it has been shown that SLC4A11 has Na + -dependent OH − cotransport activity. 29,30) Furthermore, considering that L-carnitine is likely to be transported mostly in a zwitterion state, Na + might be used to electronically neutralize carnitine/OH − symport, or to offset electrogenesis during carnitine/OH − symport or carnitine/H + antiport.…”