Transport Characteristics of Tramadol in the Blood–Brain Barrier

Kitamura, Akihiro; Higuchi, Kei; Okura, Takashi; Deguchi, Yoshiaki

doi:10.1002/jps.24129

Cited by 54 publications

(83 citation statements)

References 24 publications

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“…During measurement of prodrug uptake at acidic intracellular pH i , extracellular NH 4 Cl was removed after the NH 4 Cl preincubation because intracellular NH 3 rapidly diffuses out of the cells, resulting in accumulation of protons released from NH 4 + . 17 The ability of cationic inhibitors to affect prodrug uptake was assessed by pretreating cultures with the inhibitors (including 200 μmol/L of pyrilamine, propranolol, and imipramine, 500 μmol/L astrocytes (ACs) of hemicholinium-3, choline, L-carnitine, TEA, L-lysine, L-arginine, and spermine) for 30 minutes at 37°C, then adding prodrug I or II (80 μmol/L) and incubating another 1 hour. Cultures were rinsed three times with ice-cold PBS and processed as described above.…”

Section: Prodrug Uptake Mechanisms In Blood To Brain By Capillary Endmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energyindependent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H + /OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.

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Section: Prodrug Uptake Mechanisms In Blood To Brain By Capillary Endmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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“…Deshmukh et al 11 recently reported that the use of cocktail dosing enhances throughput in rat brain microdialysis studies, but they mainly investigated drugs with K p,uu values less than 1. On the contrary, several clinically used CNS-acting drugs, including diphenhydramine, 12 oxycodone, 13 tramadol, 14 apomorphine, 15 and memantine, 16 have been confirmed to have K p,uu greater than 1.…”

Section: Introductionmentioning

confidence: 93%

“…12,14,[17][18][19][20] Though the molecular entity of this antiport system has not yet been identified, it can generate high unbound drug concentration gradients in the brain across the BBB. This is important, because CNS drugs with K p,uu greater than 1 are not only desirable in terms of good efficacy in the brain, but also exhibit reduced peripheral side effects (i.e., the unbound drug concentration in the plasma is lower than that in the brain).…”

Section: Introductionmentioning

confidence: 99%

“…For this purpose, we focused on the proton-coupled organic cation antiport system, and selected oxycodone, diphenhydramine, tramadol, memantine, and pyrilamine as model drugs. 12,14,17,18,20 Further, in cocktail dosing studies, it is important to avoid drugedrug interactions among candidates sharing the same influx transport system at the BBB, and therefore, we checked drugedrug interactions in hCMEC/D3 cells, an in vitro BBB model, 21 because these cells are known to express the proton-coupled organic cation antiport system. 18 The K p,uu values for these drugs were evaluated and compared under single-dosing and cocktail-dosing conditions.…”

Section: Introductionmentioning

confidence: 99%

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Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic–Cationic Drugs to the Brain

Kitamura

Okura

Higuchi

et al. 2016

Journal of Pharmaceutical Sciences

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Brain microdialysis is a powerful tool to estimate brain-to-plasma unbound concentration ratio at the steady state (Kp,uu) of compounds by direct measurement of the unbound concentration in brain interstitial fluid. Here, we evaluated a method to estimate Kp,uu values of multiple organic-cationic drugs simultaneously, by means of brain microdialysis combined with cocktail dosing. Five cationic drugs (diphenhydramine, memantine, oxycodone, pyrilamine, and tramadol), substrates of the proton-coupled organic cation antiport system, were selected as model drugs, and compared under single-dosing and cocktail-dosing conditions. We selected doses of the drugs at which no significant drug-drug interaction occurs at the proton-coupled organic cation antiport system in the blood-brain barrier (BBB). This was confirmed by uptake studies in hCMEC/D3 cells, an in vitro BBB model. The Kp,uu values after cocktail administration were in the range of 1.8-5.2, and were in good agreement with those after single administration. These results suggest that the microdialysis method with cocktail dosing is suitable to estimate Kp,uu values of several cationic drugs simultaneously, if there is no drug-drug interaction during BBB transport. The method could be useful for evaluating drug candidates with high Kp,uu values at an early stage in the development of central nervous system-acting drugs.

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Involvement of a proton‐coupled organic cation antiporter in the blood–brain barrier transport of amantadine

Suzuki

Aoyama

Suzuki

et al. 2016

Biopharm & Drug Disp

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The blood-to-brain transport of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, has been shown previously to participate in the cationic drug-sensitive transport system across the mouse blood-brain barrier (BBB). The purpose of the present study was to characterize the influx transport system by means of both an in situ mouse brain perfusion technique and in vitro studies using rat immortalized brain capillary endothelial cells (GPNT). The observed concentration-dependent initial uptake rate of [(3) H]amantadine suggested the involvement of a carrier-mediated transport mechanism. The normal uptake at physiological pH 7.4 was decreased by 72.9% in acidic perfusate, while it was increased by 35.3% in alkaline perfusate. These results suggest that pH-dependent transport is regulated by utilizing an oppositely directed proton gradient as a driving force. In addition, the [(3) H]amantadine uptake was moderately inhibited by the adamantane structural analogs (rimantadine and memantine) and other cationic drugs (pyrilamine, clonidine, nicotine, etc.), but not by substrates or inhibitors of the well-characterized organic cation transporters (tetraethylammonium, l-carnitine and choline). A similar inhibition pattern was observed between the in vivo studies and the in vitro experiments. These results indicate that the influx transport for amantadine across the BBB involves a proton-coupled organic cation antiporter. Copyright © 2016 John Wiley& Sons, Ltd.

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Transport Characteristics of Tramadol in the Blood–Brain Barrier

Cited by 54 publications

References 24 publications

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

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

Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic–Cationic Drugs to the Brain

Involvement of a proton‐coupled organic cation antiporter in the blood–brain barrier transport of amantadine

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