Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation

Abstract

Uptake transporters in brain microvascular endothelial cells (BMECs) are involved in the penetration of basic (cationic) drugs such as diphenhydramine (DPHM) into the brain. Lipopolysaccharide (LPS)-induced inflammation alters the expression levels and activities of uptake transporters, which change the penetration of DPHM into the brain. A brain microdialysis study showed that the unbound brain-to-plasma partition coefficient ( K p,uu,brain ) for DPHM in LPS rats was approximately two times higher than that in control rats. The transcellular transport of DPHM to BMECs was increased when BMECs were cultured with serum from LPS rats. Compared with control rats or BMECs, the brain uptake of DPHM in LPS rats was increased and the intracellular accumulation of DPHM was increased under a high intracellular pH in BMECs from LPS rats, respectively. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. This study suggests that LPS-induced inflammation promotes unidentified proton-coupled organic cation (H + /OC) antiporters that improve the penetration of DPHM into rat brain via the blood-brain barrier.

The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells

“…Diphenhydramine was included as a positive control for active uptake via the H + /OC antiporter. Previous microdialysis studies in rats, have reported K p,uu values between 3.24-5.5 for diphenhydramine, which clearly indicate active uptake across the BBB (30)(31)(32). In our study design, where we estimate K p,uu in experiments on mice, using the K p value and calculated free concentrations, diphenhydramine displayed a K p,uu of 1.72.…”

“…The H + /OC antiporter is suggested to transport substrates such as histamine receptor antagonists (pyrilamine and diphenhydramine) (19,21,23,24), opioid agonists (oxycodone and tramadol) (19,25), memantine (an NMDA receptor antagonist) (26), pramipexol (a dopamine 2 receptor agonist) (27), and nicotinic acetylcholine receptor agonists (nicotine and varenicline) (28,29). A number of these substrates are found to not only cross the BBB, but also to accumulate in the brain, as indicated by an unbound brain-to-unbound plasma partitioning coe cient (K p,uu ) above 1 (29)(30)(31)(32). A common trait among these H + /OC antiporter substrates, is that they are small molecules bearing a secondary or tertiary amine moiety, which is positively charged at physiological relevant pH (33,34).…”

The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells

“…Diphenhydramine was included as a positive control for active uptake via the H + /OC antiporter. Previous microdialysis studies in rats, have reported K p,uu values between 3.24–5.5 for diphenhydramine, which clearly indicate active uptake across the BBB [ 30 – 32 ]. In our study design, where we estimate K p,uu in experiments on mice, using the K p value and calculated free concentrations, diphenhydramine displayed a K p,uu of 1.72.…”

Carrier-Mediated Delivery of Low-Molecular-Weight N-Containing Drugs across the Blood–Brain Barrier or the Blood–Retinal Barrier Using the Proton-Coupled Organic Cation Antiporter

“…Furthermore, GLUT1 is expressed on both the apical and basolateral membranes of capillary endothelial cells, facilitating the successive transport of its substrate from the bloodstream into the brain. Thus, it is important to identify the H + /OC antiporter as early as possible to advance research in drug delivery, although its features have already been investigated [52,53]. The pharmacophore for the H + /OC cation antiporter inhibitor was calculated using computer software based on data obtained from in vitro competitive permeation assays using labeled substrates in hCMEC/D3 cells [54].…”