Microsomal metabolism of carbamazepine and oxcarbazepine in liver and placenta.
Metabolism of both carbamazepine (CBZ) and oxcarbazepine (OCBZ) were catalyzed by human liver microsomes and microsomes from livers of CBZ-induced or non-induced C57BL/6 mice. Human placental microsomes metabolized only OCBZ. Mouse liver microsomes metabolized CBZ to carbamazepine-10,11-epoxide (CBZ-E), 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ), 3hydroxy-carbamazepine (3-OH-CBZ), 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine (10,11-D) and to an unidentified metabolite. CBZ-pretreatment of mice increased both ethoxyresorufin O-deethylase activity in the liver and the amount of CBZ-E in microsomal incubations regardless of the age of mice. Human liver microsomes catalyzed the formation of CBZ to 9-hydroxymethyl-10-carbamoyl acridan (9-AC) in addition to CBZ-E, 3-OH-CBZ and 10-OH-CBZ. OCBZ was metabolized to its active metabolite in all incubations. An unknown metabolite was also present in some of the incubations. Human liver microsomes catalyzed only minute covalent binding of CBZ and OCBZ to DNA. Binding of OCBZ was, however, one order of magnitude greater than binding of CBZ. Human placental microsomes from the mothers on CBZ therapy did not catalyze CBZ metabolism. The same microsomes catalyzed OCBZ metabolism to 10-OH-CBZ and to an unknown metabolite. These results indicate autoinduction in CBZ metabolism in mouse liver. Due to the higher binding of OCBZ than CBZ to DNA in vitro, further studies on the potential mutagenicity of OCBZ may be warranted.
Myllynen
P
P
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Pienimäki
P
P
Raunio
H
H
Vähäkangas
K
K
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D000078330:Oxcarbazepine; D010920:Placenta / Q000378:metabolism*