Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19.
Multiple studies suggest that phenytoin concentrations increase with CBZ co-medication. This study evaluated the hypothesis that CBZ and/or its major metabolite (CBZE) inhibit CYP2C19-mediated phenytoin metabolism using human liver microsomes and cDNA-expressed CYP2C19. Oxcarbazepine (OXC), and its 10-monohydroxy metabolite (MHD) were also evaluated. CBZ and MHD inhibited CYP2C19-mediated phenytoin metabolism at therapeutic concentrations. Thus, administration of CBZ and OXC with CYP2C19 substrates with narrow therapeutic ranges should be done cautiously.
Lakehal
F
F
Department of Pharmaceutics, University of Washington, Seattle, WA 98195-7610, USA.
Wurden
C J
CJ
Kalhorn
T F
TF
Levy
R H
RH
D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002734:Chlorophyll / Q000031:analogs & derivatives*; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008617:Mephenytoin / Q000031:analogs & derivatives*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000078330:Oxcarbazepine; D010672:Phenytoin / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a; D002220:Carbamazepine; D010672:Phenytoin; C025687:4-hydroxymephenytoin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D000078330:Oxcarbazepine