Interaction of Antiepileptic Drugs with Human P-Glycoprotein in Vitro

Abstract

About one-third of epilepsy patients are resistant to treatment with antiepileptic drugs (AEDs). This refractoriness is not fully understood, but is thought to be attributed to overexpression of multidrug transporters at the blood-brain barrier, particularly P-glycoprotein (Pgp). In certain cases pharmacoresistance can be overcome by add-on therapy, raising the question of whether the coadministered drugs act as inhibitors of Pgp. Indeed, several AEDs are substrates and to some extent also inducers of Pgp. To date nothing is known about possible Pgp inhibitory activities of AEDs. Therefore, we investigated whether AEDs commonly used in mono or add-on therapy inhibit Pgp using a calcein acetoxymethylester uptake assay with L-MDR1 cells and primary porcine brain capillary endothelial cells, as well as confocal laser-scanning microscopy with L-MDR1 cells and bodipy-verapamil as Pgp substrate. In the calcein assay only carbamazepine inhibited Pgp, which was confirmed in confocal laser-scanning microscopy. In this assay, also phenytoin, lamotrigine, and valproate revealed Pgp inhibitory potency. Because Pgp inhibition by AEDs appeared at significantly higher concentrations than that of well known inhibitors and because the effective concentrations exceeded therapeutic AED plasma concentrations, Pgp inhibition appears not to be of clinical relevance, at least in antiepileptic monotherapy. However, it is possible that this inhibition may contribute to the effectiveness of certain add-on therapies.

Modulation of Cellular Cholesterol Alters P-Glycoprotein Activity in Multidrug-Resistant Cells

“…For excitation, a 488-nm argon laser line was used, and a 500-to 550-nm band-pass filter was used to detect emission. The suitability of this assay to quantify P-glycoprotein activity has been shown previously (Weiss et al, 2003b).…”

EVALUATION OF INHIBITORY POTENCIES FOR COMPOUNDS INHIBITING P-GLYCOPROTEIN BUT WITHOUT MAXIMUM EFFECTS: F2 VALUES

“…Twenty-seven compounds were investigated in all three cell systems, 35 in two systems, and 16 in only one cell system. Among them were highly potent P-gp inhibitors like LY335979 (zosuquidar), SDZ-PSC833 (valspodar), and GG918 (elacridar), drugs used for HIV therapy, fungicides, newer antidepressants (Weiss et al, 2003a), progestins (Frö hlich et al, 2004), fibrates (Ehrhardt et al, 2004), amphetamines (KetabiKiyanvash et al, 2003), antiepileptic drugs (Weiss et al, 2003b), and kava-kava extracts and kavalactones (Weiss et al, 2005). Of all these compounds, 21 revealed no P-gp inhibition up to the highest soluble concentration (10 in P388/dx cells, 19 in L-MDR1 cells, and 11 in pBCECs).…”

Herb — drug interaction of noni juice and Ginkgo biloba with phenytoin

“…The involvement of P-glycoprotein (P -gp) in noni juice pretreated rats may be ruled out because phenytoin is a weak inhibitor of p-gp. [50] If the involvement of P-gp is speculated then the bioavailability of phenytoin should have been increased but in the present study the bioavailability of phenytoin is decreased. Hence for each group.…”