title: Exposure to antiepileptic drugs does not alter the functionality of P-glycoprotein in brain capillary endothelial and kidney cell lines.
abstract: 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. As a consequence, it is important to know whether antiepileptic drugs alter the expression or functionality of Pgp in endothelial cells. In the present study, we studied the effects of exposure to phenobarbital, phenytoin and carbamazepine on Pgp expression and functionality in the rat brain endothelial cell line GPNT. For comparison with drug effects on endothelial cells, a dog kidney cell line (MDCK II) was used. Furthermore, several known Pgp inducers (dexamethasone, doxorubicin, and rifampicin) were included in the study. Functionality of Pgp was determined by uptake assays, using known Pgp substrates (digoxin and vinblastine) and transport inhibitors (tariquidar, MK571). In GPNT cells, exposure to dexamethasone increased Pgp functionality, while antiepileptic drug exposure at clinically relevant concentrations did not exert any significant induction of Pgp expression or function. Similarly, antiepileptic drug exposure did not affect Pgp in MDCK cells. The lack of antiepileptic drugs to induce Pgp in brain capillary endothelial cells and kidney cells is in contrast to their known effect on Pgp expression in hepatic and intestinal cells, substantiating tissue differences in the regulation of Pgp.
authors: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany.
authors: Kamila
authors: K
authors: Ambroziak
authors: Konstantin
authors: K
authors: Kuteykin-Teplyakov
authors: Carlos
authors: C
authors: Luna-Tórtos
authors: Marwan
authors: M
authors: Al-Falah
authors: Maren
authors: M
authors: Fedrowitz
authors: Wolfgang
authors: W
authors: Löscher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D003907:Dexamethasone / Q000494:pharmacology; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D000090702:Constitutive Androstane Receptor; C000716329:Nr1i3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D003907:Dexamethasone