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In Vivo Evidence for P‐Glycoprotein–Mediated Transport of Phenytoin at the Blood–Brain Barrier of Rats
Author(s) -
Potschka Heidrun,
Löscher Wolfgang
Publication year - 2001
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2001.01901.x
Subject(s) - microdialysis , blood–brain barrier , phenytoin , pharmacology , in vivo , verapamil , anticonvulsant , p glycoprotein , epilepsy , chemistry , medicine , endocrinology , central nervous system , biology , biochemistry , calcium , microbiology and biotechnology , antibiotics , psychiatry , multiple drug resistance
Summary: Purpose: The multidrug transporter P‐glycoprotein (P‐gp) is expressed at high levels in a variety of tissues such as the endothelial cells of the blood–brain barrier (BBB) capillaries, where it is thought to be involved in the exclusion of various drugs from the capillary endothelial cells, blocking their entry into brain. It was previously shown that pharmacoresistant partial epilepsy is associated with an increased expression of P‐gp in brain capillary endothelium and astrocytes, leading to the hypothesis that increased P‐gp expression may be involved in medically intractable epilepsy. However, it is not known whether the distribution of antiepileptic drugs (AEDs) into the brain is limited by P‐gp. We used in vivo microdialysis in freely moving rats to study whether the concentration of the major AED phenytoin (PHT) in the extra‐cellular fluid (ECF) of the cerebral cortex can be enhanced by inhibition of P‐gp. Methods: Three different P‐gp inhibitors, sodium cyanide, verapamil, and PSC 833, were used. These drugs were given via the microdialysis probe in the right frontal cortex, while a probe in the left cortex served as vehicle control side. Perfusion with the inhibitor started 15–60 min before systemic (i.p.) administration of PHT, 50 mg/kg. Results: PHT rapidly entered the brain ECF compartment, but ECF plasma ratios at time of maximal ECF levels were only ∼0.04. All P‐gp inhibitors significantly increased the ECF concentrations of PHT after local administration, indicating that P‐gp in the BBB normally limits the distribution of PHT into the brain parenchyma. Cremorphor EL, the vehicle used to administer PSC, also was able to increase ECF PHT, which is explained by the previously reported inhibitory effect of cremophor on P‐gp. Conclusions: Provided that multidrug transporters such as P‐gp also are involved in the BBB outward transport of other AEDs, increased expression of multidrug transporters, leading to inadequate accumulation of AEDs in the brain, would be a likely explanation for pharmacoresistant epilepsy.