Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition

• Published in: Acta neurologica Scandinavica Vol. 115; no. 4; pp. 232 - 242
• Main Authors: Simon, C., Stieger, B., Kullak-Ublick, G. A., Fried, M., Mueller, S., Fritschy, J.-M., Wieser, H.G., Pauli-Magnus, C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2007; Blackwell
• Subjects: Adult; Aged; Anticonvulsants - administration & dosage; Anticonvulsants - blood; antiepileptic drugs; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; carbamazepine; Carbamazepine - administration & dosage; Carbamazepine - blood; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Dose-Response Relationship, Drug; Duodenum - metabolism; Endocrinopathies; epilepsy; Epilepsy - drug therapy; Epilepsy - genetics; Epilepsy - metabolism; Female; Humans; Hypothalamus. Hypophysis. Epiphysis (diseases); intestinal absorption; Male; MDR1; Medical sciences; Middle Aged; MRP2; Neurology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; pharmacokinetics; phenytoin; Phenytoin - administration & dosage; Phenytoin - blood; Polymorphism, Genetic - genetics; Tumors of the nervous system. Phacomatoses; Drug; antiepileptic drugs; Nervous system diseases; MRP2; Digestive system; Enzyme; Cytochrome P450; Epilepsy; Gut; Anticonvulsant; Carbamazepine; Cerebral disorder; MDR1; Absorption; Central nervous system disease; intestinal absorption; Pharmacokinetics; ABC transporter; Multidrug resistance protein 2; Phenytoin
• ISSN: 0001-6314; 1600-0404
• DOI: 10.1111/j.1600-0404.2006.00761.x

Objectives –  Interindividual variability in intestinal absorption and bioavailability might contribute to inadequate control of seizures under treatment with carbamazepine and phenytoin. We therefore correlated intestinal expression levels and genetics of CYP3A4, CYP2C9/19, MDR1 and MRP2 with dose requirement and plasma levels of carbamazepine and phenytoin. Materials and methods –  Epileptic patients on carbamazepine (n = 29) or phenytoin (n = 15) were stratified into a ‘high’‐dose (carbamazepine ≥800 mg/day, phenytoin ≥300 mg/day) and a ‘low’‐dose group (carbamazepine ≤600 mg/day, phenytoin ≤200 mg/day). Duodenal biopsies and DNA were obtained for Western blotting and genotyping studies. Results –  Low carbamazepine plasma levels showed a trend towards higher intestinal MDR1 expression (P = 0.06). Furthermore, carbamazepine dose was positively correlated with MRP2 expression (P = 0.1). Moreover, MDR1 expression and carbamazepine and phenytoin dose requirement was influenced by the genotype in position 2677 and 3435 of the MDR1 gene. Conclusion –  Differences in intestinal MDR1 and MRP2 expression may influence carbamazepine and phenytoin disposition and may account for interindividual pharmacokinetic variability.