Diphenhydramine Active Uptake at the Blood–Brain Barrier and Its Interaction with Oxycodone in vitro and in Vivo

Sadiq, Muhammad Waqas; Borgs, Annika; Okura, Takashi; Shimomura, Keita; Kato, Sayaka; Deguchi, Yoshiaki; Jansson, Bjarne; Björkman, Sven; Terasaki, Tetsuya; Hammarlund‐Udenaes, Margareta

doi:10.1002/jps.22567

Cited by 84 publications

(116 citation statements)

References 28 publications

(31 reference statements)

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Modifying the vascular or intracellular proton concentration by diverse physical or biochemical protocols altered the transport of nicotine at the BBB in a way that suggests the presence of a sodium-independent nicotine/proton antiporter with features similar to those of the diphenhydramine and clonidine/proton antiporter at the mouse BBB (7). A similar transporter has also been found in BBB cell lines, where it transports oxycodone, diphenhydramine, and codeine (33)(34)(35). An analogous nicotine/proton antiporter has also been characterized in kidney tubules, Caco-2, JAR, and LLC-PK1 cell lines (8,36,37).…”

Section: Discussionmentioning

confidence: 80%

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

Cisternino

Chapy

André

et al. 2012

AAPS J

View full text Add to dashboard Cite

Abstract. Nicotine, the main tobacco alkaloid leading to smoking dependence, rapidly crosses the bloodbrain barrier (BBB) to become concentrated in the brain. Recently, it has been shown that nicotine interacts with some organic cation transporters (OCT), but their influence at the BBB has not yet been assessed in vivo. In this study, we characterized the transport of nicotine at the mouse luminal BBB by in situ brain perfusion. Its influx was saturable and followed the Michaelis-Menten kinetics (K m 02.60 mM, V max 037.60 nmol/s/g at pH 7.40). At its usual micromolar concentrations in the plasma, most (79%) of the net transport of nicotine at the BBB was carrier-mediated, while passive diffusion accounted for 21%. Studies on knockout mice showed that the OCT Oct1-3, P-gp, and Bcrp did not alter [3 H]-nicotine transport at the BBB. Neither did inhibiting the transporters Mate1, Octn, or Pmat. The in vivo manipulation of intracellular and/or extracellular pH, the chemical inhibition profile, and the transstimulation experiments demonstrated that the nicotine transporter at the BBB shared the properties of the clonidine/proton antiporter. The molecular features of this proton-coupled antiporter have not yet been identified, but it also transports diphenhydramine and tramadol and helps nicotine cross the BBB at a faster rate and to a greater extent. The pharmacological inhibition of this nicotine/proton antiporter could represent a new strategy to reduce nicotine uptake by the brain and thus help curb addiction to smoking.

show abstract

Section: Discussionmentioning

confidence: 80%

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

Cisternino

Chapy

André

et al. 2012

AAPS J

View full text Add to dashboard Cite

show abstract

“…Several drugs have been reported to be proton-coupled organic cation antiporter substrates, including pramipexole, 13) oxycodone, 6) pyrilamine, 4,6) 3,4-methylenedioxymethamphetamine, 9) clonidine, 10) diphenhydramine, 4,7,14) nicotine, 15,16) and propranolol.…”

Section: Discussionmentioning

confidence: 99%

Proton-Coupled Organic Cation Antiporter-Mediated Uptake of Apomorphine Enantiomers in Human Brain Capillary Endothelial Cell Line hCMEC/D3

Okura

Higuchi

Kitamura

et al. 2014

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

R( )-Apomorphine is a dopamine agonist used for rescue management of motor function impairment associated with levodopa therapy in Parkinson's disease patients. The aim of this study was to examine the role of proton-coupled organic cation antiporter in uptake of R( )-apomorphine and its S-enantiomer in human brain, using human endothelial cell line hCMEC/D3 as a model. Uptake of R( )-or S( )-apomorphine into hCMEC/D3 cells was measured under various conditions to evaluate its time-, concentration-, energy-and ion-dependency. Inhibition by selected organic cations was also examined. Uptakes of both R( )-and S( )-apomorphine increased with time. The initial uptake velocities of R( )-and S( )-apomorphine were concentration-dependent, with similar K m and V max values. The cell-to-medium (C/M) ratio of R( )-apomorphine was significantly reduced by pretreatment with sodium azide, but was not affected by replacement of extracellular sodium ion with N-methylglucamine or potassium. Intracellular alkalization markedly reduced the uptake, while intracellular acidification increased it, suggesting that the uptake is driven by an oppositely directed proton gradient. The C/M ratio was significantly decreased by amantadine, verapamil, pyrilamine and diphenhydramine (substrates or inhibitors of proton-coupled organic cation antiporter), while tetraethylammonium (substrate of organic cation transporters (OCTs)) and carnitine (substrate of carnitine/organic cation transporter 2; (OCTN2)) had no effect. R( )-Apomorphine uptake was competitively inhibited by diphenhydramine. Our results indicate that R( )-apomorphine transport in human blood-brain barrier (BBB) model cells is similar to S( )-apomorphine uptake. The transport was dependent on an oppositely directed proton gradient, but was sodium-or membrane potential-independent. The transport characteristics were consistent with involvement of the previously reported proton-coupled organic cation antiporter.Key words apomorphine; blood-brain barrier; proton-coupled organic cation antiporter; hCMEC/D3 cell R(−)-Apomorphine, a dopamine agonist, has been approved as a subcutaneous injection formulation for rescue management of motor function impairment associated with levodopa therapy in patients with Parkinson's disease. It has been reported to have a 12 times higher unbound concentration in the brain than the blood (brain-to-blood unbound concentration ratio, K puu =12, 1) whereas S(+)-apomorphine, the dopamine receptor-inactive enantiomer, has a K puu of 5.1) These results suggest that both enantiomers are actively transported into the brain across the blood-brain barrier (BBB) in rats. However, the mechanism of blood-to-brain transport of this drug across the BBB remains unknown.The immortalized human brain capillary endothelial cell line, hCMEC/D3 has been extensively validated as a BBB model by means of pharmacological, toxicological, immunological and infection studies in numerous laboratories worldwide, and it is established that hCMEC/D3 cells retain many of the morphologi...

show abstract

“…CE-157119 also had a constant C b,ufavoring C b,u /C p,u in all studied animals suggesting it is a speciesindependent net active influx substrate at the BBB, but not the blood-CSF barrier. Reminiscent of oxycodone [pK a 8.5 (Tien, 1991)] and diphenhydramine [pK a 9.0 (de Roos et al, 1970)], basic amines that exhibit C m /C p,u Ն2.8 in rats and are substrates for a BBB amine/H ϩ antiporter (Boström et al, 2006;Sadiq et al, 2011), CE-157119 is an acyclic secondary amine (pK a 8.6) predominantly (94%) protonated at physiological pH, feasibly making it a substrate for a similar (if not identical) BBB cation-uptake transporter. If this is true, the CE-157119 neuropharmacokinetic dataset implies the commonality of this BBB influx transporter in rats, dogs, and nhp.…”

Section: Discussionmentioning

confidence: 99%

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

et al. 2012

View full text Add to dashboard Cite

ABSTRACT:Previous publications suggest that interstitial fluid compound concentrations (C ISF ) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C ISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C b,u / C p,u ) to project accurately dog and nonhuman primate (nhp) C b,u , a C ISF surrogate, from measured C p,u for the highly permeable non-Pglycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-

show abstract

Diphenhydramine Active Uptake at the Blood–Brain Barrier and Its Interaction with Oxycodone in vitro and in Vivo

Cited by 84 publications

References 28 publications

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

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

Proton-Coupled Organic Cation Antiporter-Mediated Uptake of Apomorphine Enantiomers in Human Brain Capillary Endothelial Cell Line hCMEC/D3

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

Contact Info

Product

Resources

About