Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats

Potschka, Heidrun; Baltes, Steffen; Löscher, Wolfgang

doi:10.1016/j.eplepsyres.2003.12.007

Cited by 84 publications

(47 citation statements)

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“…Indeed, in physiological conditions the EC hippocampal/plasma ratio for OXC is approximately 10%. In contrast, for levetiracetam, which was shown not to be a substrate for the currently investigated MDTs, this ratio was about 20% (Potschka et al, 2004). Our data are in line with the EC hippocampal/plasma ratios for other AEDs, which are substrates for MDTs.…”

Section: Discussionsupporting

confidence: 74%

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Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Clinckers¹,

Smolders²,

Meurs³

et al. 2005

J Pharmacol Exp Ther

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Various antiepileptic drugs were shown to be substrates for multidrug transporters at the level of the blood-brain barrier. These ATP-dependent efflux pumps actively limit brain accumulation of xenobiotics and drugs. Intrahippocampal oxcarbazepine perfusion in rat was previously shown to exert anticonvulsant effects associated with increases in extracellular dopamine and serotonin levels. In contrast, preliminary studies in our laboratory revealed that no anticonvulsant or monoaminergic effects could be obtained after systemic oxcarbazepine administration. The present in vivo microdialysis study was conducted to investigate the impact of the transport kinetics of oxcarbazepine across the blood-brain barrier on the observed treatment refractoriness. More precisely, the influence of intrahippocampal perfusion of verapamil, a P-glycoprotein inhibitor, and probenecid, a multidrug resistance protein inhibitor, on the blood-brain barrier passage and anticonvulsant properties of oxcarbazepine were investigated in the focal pilocarpine model for limbic seizures. Simultaneously, the effects on hippocampal monoamines were studied as pharmacodynamic markers for the anticonvulsant activity. Although systemic oxcarbazepine administration alone failed in preventing the animals from developing seizures, coadministration with verapamil or probenecid offered complete protection. Concomitantly, significant increases in extracellular hippocampal dopamine and serotonin levels were observed within our previously defined anticonvulsant monoamine range. The present data indicate that oxcarbazepine is a substrate for multidrug transporters at the bloodbrain barrier. Coadministration with multidrug transporter inhibitors significantly potentiates the anticonvulsant activity of oxcarbazepine and offers opportunities for treatment of pharmacoresistant epilepsy.Oxcarbazepine (OXC) is the 10,11-keto analog of carbamazepine (CBZ). Like CBZ, it is considered to exert its antiepileptic effects by stabilization of the Na ϩ channels in a voltage-, frequency-, and time-dependent manner. OXC can also block high-threshold Ca 2ϩ currents and increase K ϩ channel conductance (McLean et al., 1994). Previously, we showed that increases in hippocampal dopamine (DA) and serotonin (5-HT) levels can have important anticonvulsant effects in the focal pilocarpine model for limbic psychomotor seizures (Clinckers et al., 2004a). These anticonvulsant effects were restricted to a well defined anticonvulsant concentration range and were proven to be mediated by D 2 and 5-HT 1A receptor stimulation. Anticonvulsant activity against pilocarpine-induced seizures can also be achieved by intrahippocampal perfusion of OXC (unpublished data). From the anticonvulsant threshold concentration (i.e., 100 M) onward, significant increases in extracellular (EC) hippocampal DA and 5-HT levels were observed, within the previously determined anticonvulsant monoamine ranges. These monoaminergic neurotransmitter increases were again shown to importantly contribute to the ant...

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Section: Discussionsupporting

confidence: 74%

“…In the current experimental design, verapamil and probenecid are used as Pgp and MRP inhibitors, respectively (Bebawy et al, 2001;Gerk and Vore, 2002;Potschka et al, 2004). Although more selective blockers exist, these compounds are widely used as standard inhibitors of these MDTs.…”

mentioning

confidence: 99%

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Clinckers¹,

Smolders²,

Meurs³

et al. 2005

J Pharmacol Exp Ther

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“…Until recently, most of the studies linking BBB to drug resistant epilepsy have focused on transport barrier mechanisms [11,[14][15][16][17][18][19][20][21][22]. Transcript levels of P450 enzymes known to be responsible for the metabolism of several AEDs enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2A6 and CYP2E1) were demonstrated to be elevated in brain endothelial cells isolated from temporal lobe resections of drug resistant epileptic subjects compared to commercially available, "control" human brain endothelium [23,24].…”

Section: New Vistas On Drug Biotransformation: Brain P450 Enzymesmentioning

confidence: 99%

“…AED therapeutic failure may thus be due to a modification of neuronal targets (pharmacodynamic hypothesis) [10][11][12][13] or to inadequate AED brain levels (pharmacokinetic hypothesis). Overexpression of multidrug transporter (MDTs) proteins at the BBB was considered to be a mechanism responsible for the possible AED brain misdistribution [11,[14][15][16][17][18]: overexpression of multi-drug transporters at the BBB luminal side de facto impedes drugs penetration into the brain parenchyma [17,[19][20][21]. …”

mentioning

confidence: 99%

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Ghosh¹

2011

CDM

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Drug penetration into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Even though a number of strategies to circumvent the BBB and to improve drug access have been developed, drug resistance in CNS diseases remains an unmet clinical problem. We here review the mechanisms by which a healthy or pathological BBB influences drug distribution in the brain, with emphasis on the role of P450 metabolic enzymes and multi-drug transporter (MDT) proteins. In addition to the classic hepatic and gut biotransformation pathways, CNS expression of P450 enzymes may bear pharmacokinetic and pharmacodynamic significance exerting a metabolic activity and transforming parent drugs into specific products. We propose these mechanisms to play a major role in CNS drug resistant pathologies including refractory forms of epilepsy.Changes in the cerebrovascular hemodynamic conditions can affect expression of P450 enzymes and MDT proteins. This should be taken into account when developing in vitro experimental approaches to reproduce the physiological or pathological properties of the BBB. Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed. KeywordsBlood-brain barrier; drug resistant epilepsy; multidrug transporters proteins (MDT); P450 enzymes THE BLOOD-BRAIN BARRIER: A BRIEF OVERVIEWThe brain microvascular endothelial cells that constitute the blood-brain barrier (BBB) are responsible for the passage of xenobiotics and nutrients from the blood into the brain parenchyma, and vice versa. At the cellular level, the BBB consists of endothelial cells HHS Public Access DRUG RESISTANCE IN CNS DISEASESDrug resistance in brain diseases is an unsolved clinical problem. For example, drug resistant epilepsy affects approximately 20-25% of epileptics. According to the recent consensus of the International League Against Epilepsy (ILAE), "drug resistant epilepsy is defined with the failure of adequate trials of two appropriately chosen antiepileptic drugs, whether as monotherapies or in combination, to achieve sustained seizure freedom" [7]. In the past two decades, new antiepileptic drugs (AEDs) have been developed but no major reduction in the percentage of drug-resistant patients has been achieved [8,9]. The complexity of the drug resistant epileptic phenotype reflects the nature of the pathophysiological process, its possible evolution over time and individual sensitivity to drugs. In order to explain the mechanisms underlying the drug resistant condition, a pharmacokinetic and a pharmacodynamic hypothesis were proposed more than a decade ago. AED therapeutic failure may thus be due to a modification of neuronal targets (pharmacodynamic hypothesis) [10][11][12][13] or to inadequate AED brain levels (pharmacokinetic hypothesis). Overexpression of multidrug transporter (MDTs) proteins at the BBB was considered to be a mechanism responsible for the possible AED brain misdistribution [11,[14][15][16][17][18]: overexpression of multi-drug transporters at the BBB...

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“…83 Recent data from our group showed that levetiracetam is the first AED tested in our lab that is not a substrate for Pgp. 84 Thus, development of AEDs that bypass overexpressed multidrug transporters could be a valuable approach for overcoming drug resistance. For direct proof of principle, we currently examine whether Pgp inhibitors can be used to counteract multidrug resistance in drug resistant kindled rats.…”

Section: Role Of the Bbb Abc Transporters In Drug Resistancementioning

confidence: 99%

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

Self Cite

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats

Cited by 84 publications

References 32 publications

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

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