Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Problems and approaches in determining which antiepileptic drugs are affected.

Resistance to multiple antiepileptic drugs (AEDs) is a common problem in epilepsy, affecting at least 30% of patients. One prominent hypothesis to explain this resistance suggests an inadequate penetration or excess efflux of AEDs across the blood - brain barrier (BBB) as a result of overexpressed efflux transporters such as P-glycoprotein (Pgp), the encoded product of the multidrug resistance- 1 (MDR1, ABCB1) gene. Pgp and MDR1 are markedly increased in epileptogenic brain tissue of patients with AED-resistant partial epilepsy and following seizures in rodent models of partial epilepsy.

Differences in the expression of endogenous efflux transporters in MDR1-transfected versus wildtype cell lines affect P-glycoprotein mediated drug transport.

Background And Purpose: P-glycoprotein (Pgp) efflux assays are widely used to identify Pgp substrates. The kidney cell lines Madin-Darby canine kidney (MDCK)-II and LLC-PK1, transfected with human MDR1 (ABCB1) are used to provide recombinant models of drug transport. Endogenous transporters in these cells may contribute to the activities of recombinant transporters, so that drug transport in MDR1-transfected cells is often corrected for the transport obtained in parental (wildtype) cells.

Evaluation of transport of common antiepileptic drugs by human multidrug resistance-associated proteins (MRP1, 2 and 5) that are overexpressed in pharmacoresistant epilepsy.

Resistance to antiepileptic drugs (AEDs) is one of the most serious problems in the treatment of epilepsy. Accumulating experimental evidence suggests that increased expression of the drug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier may be involved in the mechanisms leading to AED resistance. In addition to Pgp, increased expression of several multidrug resistance-associated proteins (MRPs) has been determined in epileptogenic brain regions of patients with pharmacoresistant epilepsy.

Exposure to antiepileptic drugs does not alter the functionality of P-glycoprotein in brain capillary endothelial and kidney cell lines.

Several major antiepileptic drugs, including carbamazepine, phenytoin and phenobarbital, induce xenobiotic metabolizing enzymes via activation of nuclear receptors, including pregnane X receptor (NR1I2) and constitutive androstane receptor (NR1I3). Via activation of these xenobiotic sensors, antiepileptic drugs may also induce the expression of efflux transporters such as P-glycoprotein (Pgp) in different tissues, including intestine, liver, kidney and brain. Increased expression of Pgp in brain capillary endothelial cells, which form the blood-brain barrier, could limit the penetration of antiepileptic drugs into the brain and therefore decrease their therapeutic efficacy.

The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins.

Purpose: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs).In this respect, it is important to know which AEDs are substrates for such drug transporters in humans.

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

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.

Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays.

The antiepileptic drug valproic acid (VPA) is widely used in the treatment of epilepsy, bipolar disorders, and migraine. However, rather high doses are required for the clinical effects of VPA, which is due to its relatively inefficient delivery to the brain. The poor brain distribution of VPA is thought to reflect an asymmetric transport system at the blood-brain barrier (BBB).