Several major antiepileptic drugs are substrates for human P-glycoprotein.

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Luna-Tortos C, Fedrowitz M, Loscher W

Several major antiepileptic drugs are substrates for human P-glycoprotein.

Neuropharmacology. 2008 Dec;55(8):1364-75. doi: 10.1016/j.neuropharm.2008.08.032. Epub 2008 Sep 11.

PubMed ID

18824002 [ View in PubMed

]

Abstract

One of the current hypotheses of pharmacoresistant epilepsy proposes that transport of antiepileptic drugs (AEDs) by drug efflux transporters such as P-glycoprotein (Pgp) at the blood-brain barrier may play a significant role in pharmacoresistance in epilepsy by extruding AEDs from their intended site of action. However, several recent in vitro studies using cell lines that overexpress efflux transporters indicate that human Pgp may not transport AEDs to any relevant extent. In this respect it has to be considered that most AEDs are highly permeable, so that conventional bi-directional transport assays as used in these previous studies may fail to identify AEDs as Pgp substrates, particularly if these drugs are not high-affinity substrates for Pgp. In the present study, we used a modified transport assay that allows evaluating active transport independently of the passive permeability component. In this concentration equilibrium transport assay (CETA), the drug is initially added at identical concentration to both sides of a polarized, Pgp-overexpressing cell monolayer instead of applying the drug to either the apical or basolateral side for studying bi-directional transport. Direct comparison of the conventional bi-directional (concentration gradient) assay with the CETA, using MDR1-transfected LLC cells, demonstrated that CETA, but not the conventional assay, identified phenytoin and phenobarbital as substrates of human Pgp. Furthermore, directional transport was determined for lamotrigine and levetiracetam, but not carbamazepine. Transport of AEDs could be completely or partially (>50%) inhibited by the selective Pgp inhibitor, tariquidar. However, transport of phenobarbital and levetiracetam was also inhibited by MK571, which preferentially blocks transport by multidrug resistance transporters (MRPs), indicating that, in addition to Pgp, these AEDs are substrates of MRPs. The present study provides the first direct evidence that several AEDS are substrates of human Pgp, thus further substantiating the transporter hypothesis of pharmacoresistant epilepsy.

DrugBank Data that Cites this Article

Drugs

Levetiracetam

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Lamotrigine	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Levetiracetam	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details
Phenobarbital	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inducer	Details
Phenytoin	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Lamotrigine Ezogabine	The serum concentration of Lamotrigine can be decreased when it is combined with Ezogabine.