In vitro concentration dependent transport of phenytoin and phenobarbital, but not ethosuximide, by human P-glycoprotein

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• 作者：Chunbo Zhang ; Patrick Kwan ; Zhong Zuo ; Larry Baum
• 关键词：P-glycoprotein ; Blood– ; brain barrier ; Drug transport ; Phenytoin ; Phenobarbital ; Ethosuximide ; Antiepileptic drugs
• 刊名：Life Sciences
• 出版年：2010
• 出版时间：5 June 2010
• 年：2010
• 卷：86
• 期：23-24
• 页码：899-905
• 全文大小：1120 K

文摘

Aims

One possible mechanism for epilepsy drug resistance is overexpression of P-glycoprotein in the blood–brain barrier, but whether (or which) antiepileptic drugs (AEDs) are transported by P-gp remains unclear. We evaluated AEDs as P-gp substrates using cell monolayers.

Main methods

Bi-directional transport assays and concentration equilibrium transport assays (CETAs) were performed for phenytoin (PHT), phenobarbital (PB), and ethosuximide (ESM) using wildtype Madin–Darby Canine Kidney II cell line MDCKII and porcine renal endothelial cell line LLC–PK1 cells and these cells transfected with human MDR1 cDNA to express P-gp.

Key findings

Wildtype cells demonstrated no efflux transport of PHT, PB, or ESM. In CETAs, both MDR1-transfected cell lines transported PHT from basolateral to apical when PHT loading concentrations were 5 or 10, but not 20 µg/ml. MDCK–MDR1 cells transported PB when initial concentrations were 10 or 20, but not 5 µg/ml. LLC–MDR1 did not transport PB. P-gp inhibitor verapamil blocked efflux transport. MDR1-transfected cells did not transport ESM at 5.6 or 56 µg/ml. Bi-directional transport assays demonstrated weak transport for PHT but not PB or ESM.

Significance

Human P-gp transports PHT and PB, but not ESM, in a concentration dependent manner. CETA may be more sensitive than bi-directional assays to detect transport of drugs with high passive diffusion. Potential P-gp substrates should be tested at clinically relevant concentration ranges.