title: Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine.
abstract: BIA 2-093 and BIA 2-059 are two stereoisomers under development as new antiepileptic drugs. They act as prodrugs for the corresponding hydroxy derivatives (S(+)- or R(-)-10,11-dihydro-10-hydroxy carbamazepine, respectively) which are known to be the active metabolites of the antiepileptic drug oxcarbazepine (OXC). The purpose of this study was to define the metabolic pathway especially in terms of stereoselectivity, and to estimate the possibility of racemization in humans. For in vivo studies, the rat, mouse and rabbit were chosen as models in order to cover a broad spectrum of metabolic activity. In addition, incubations with liver microsomes from these three species plus dog and monkey were compared to results obtained with human liver microsomes. It was found that both drugs were almost instantly hydrolysed to the corresponding 10-hydroxy compounds in mice, rats and rabbits. Mice and rabbits were not able to oxidize the 10-hydroxy compounds to OXC in significant amounts. In the rat, BIA 2-093 also gave origin to OXC, whereas BIA 2-059 resulted in the formation of OXC and the trans-diol metabolite in equal amounts. It could be shown that the rat is able to reduce the formed OXC in liver to S(+)-10-hydroxy metabolite, resulting in a loss of enantiomeric purity after treatment with BIA 2-059 rather than in the case of BIA 2-093. Human liver microsomes hydrolysed BIA 2-093 and BIA 2-059 to their corresponding 10-hydroxy compounds and to OXC in a very small extent with BIA 2-093 only. Therefore, BIA 2-093 and BIA 2-059 seem to be preferable drugs over OXC since they most likely exhibit a 'cleaner' metabolism. From a therapeutic point of view BIA 2-059 would be less appropriate than BIA 2-093 for the purpose of treating epileptic patients due to its propensity to undergo inactivation to the trans-diol.
authors.affiliation: Department of Research and Development, Laboratórios Bial, A Av. da Siderurgia Nacional, 4745-457 S., Mamede do Coronado, Portugal.
authors.forename: D
authors.initials: D
authors.lastname: Hainzl
authors.forename: A
authors.initials: A
authors.lastname: Parada
authors.forename: P
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D003984:Dibenzazepines / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: C039775:10,11-dihydro-10-hydroxycarbamazepine; D000927:Anticonvulsants; D003984:Dibenzazepines; D002220:Carbamazepine; C416835:eslicarbazepine acetate