IngentaConnect Intestinal expression of cytochrome P450 enzymes and ABC transpor...

Authors: Simon, C.¹; Stieger, B.²; Kullak-Ublick, G. A.; Fried, M.³; Mueller, S.¹; Fritschy, J.-M.⁴; Wieser, H.G.¹; Pauli-Magnus, C.²

Source: Acta Neurologica Scandinavica, Volume 115, Number 4, April 2007 , pp. 232-242(11)

Publisher: Blackwell Publishing

Abstract:

Simon C, Stieger B, Kullak-Ublick GA, Fried M, Mueller S, Fritschy J-M, Wieser HG, Pauli-Magnus C. Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition.

Acta Neurol Scand: DOI:10.1111/j.1600-0404.2006.00761.x.

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.

Keywords: antiepileptic drugs; epilepsy; carbamazepine; phenytoin; intestinal absorption; cytochrome P450; MDR1; MRP2; pharmacokinetics

Document Type: Research article

DOI: 10.1111/j.1600-0404.2006.00761.x

Affiliations: 1: Department of Neurology, University Hospital Zurich, Zurich, Switzerland 2: Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland 3: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland 4: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

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