title: Chronic administration of phenytoin induces efflux transporter overexpression in rats.
abstract: BACKGROUND
  Efflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response.
  
  
  METHODS
  Forty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75mg/kg/6h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25mg/kg/6h or 100mg/kg/24h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100mg/kg and plasma level were measured.
  
  
  RESULTS
  An induction of the expression of efflux transporter mediated by phenytoin in a concentration-and-time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered.
  
  
  CONCLUSIONS
  Overexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy.
authors.affiliation: Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.
authors.forename: Silvana
authors.initials: S
authors.lastname: Alvariza
authors.affiliation: Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fagiolino
authors.affiliation: Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.
authors.forename: Marta
authors.initials: M
authors.lastname: Vázquez
authors.affiliation: Medical Research Unit for Neurological Diseases, Speciality Hospital, 21st Century National Medical Center of the Mexican Institute of Social Security, Mexico City, Mexico.
authors.forename: Iris
authors.initials: I
authors.lastname: Feria-Romero
authors.affiliation: Medical Research Unit for Neurological Diseases, Speciality Hospital, 21st Century National Medical Center of the Mexican Institute of Social Security, Mexico City, Mexico. Electronic address: sorozco5@hotmail.com.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orozco-Suárez
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D007274:Injections, Intraperitoneal; D026901:Membrane Transport Proteins / Q000378:metabolism*; D010672:Phenytoin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D026901:Membrane Transport Proteins; D010672:Phenytoin
keywords: Antiepileptic drugs; Efflux transporters; Pharmacokinetics; Phenytoin; Rats