Substrate Specificity and Mechanism of the Intestinal Clonidine Uptake by Caco-2 Cells

Fischer, Wiebke; Metzner, Linda; Hoffmann, Kathrin; Neubert, Reinhard H.H.; Brandsch, Matthias

doi:10.1007/s11095-005-8925-x

Cited by 18 publications

(15 citation statements)

References 23 publications

(33 reference statements)

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“…An analogous nicotine/proton antiporter has also been characterized in kidney tubules, Caco-2, JAR, and LLC-PK1 cell lines (8,36,37). Many cationic organic drugs, such as clonidine, diphenhydramine, and MDMA, are similarly transported by a proton antiporter in Caco-2 cells (38)(39)(40). The trans-stimulation of the BBB transport of nicotine by diphenhydramine, naloxone, or tramadol suggests that they share the same transporter.…”

Section: Discussionmentioning

confidence: 96%

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

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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.

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Section: Discussionmentioning

confidence: 96%

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

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“…However, studies on the transport of secondary or tertiary amine drugs, such as methylenedioxymethamphetamine (MDMA, ecstasy), oxycodone, and clonidine, led to the discovery of an H + antiporter that is not inhibited by TEA. Its functional properties differ from those of any of the already identified organic cation transporters (Fischer et al, 2006;Okura et al, 2008;Kuwayama et al, 2008). However, as the molecular nature of the transporter involved has not been identified, it is commonly known as the 'tertiary or secondary amine/H + ' antiporter.…”

Section: Introductionmentioning

confidence: 91%

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

André

Debray

Scherrmann

et al. 2009

J Cereb Blood Flow Metab

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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.

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“…Methylenedioxymethamphetamine is one of them and its transport was inhibited by DPHM in a concentration‐dependent manner 8. Oxycodone, a tertiary amine, and clonidine were also found to be transported by this H + antiporter, which has different functional properties than previously known organic cation transporters (OCTs) 9,10. Andre et al11 suggested that clonidine transport across the luminal BBB involves a distinct amine/H + antiporter, and that this transporter interacts with organic compounds that have secondary or tertiary amine moieties.…”

Section: Introductionmentioning

confidence: 92%

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

Sadiq

Borgs

Okura

et al. 2011

Journal of Pharmaceutical Sciences

103

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Substrate Specificity and Mechanism of the Intestinal Clonidine Uptake by Caco-2 Cells

Cited by 18 publications

References 23 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

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

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

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Substrate Specificity and Mechanism of the Intestinal Clonidine Uptake by Caco-2 Cells

Cited by 18 publications

References 23 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

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

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

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Product

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