Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine

BIA 2-093 and BIA 2-059 are two stereoisomers under development as new anti epileptic drugs. They act as prodrugs for the corresponding hydroxy derivat ives (S(+)- or R(-)-10,11-dihydro-10-hydroxy carbamazepine, respectively) w hich are known to be the active metabolites of the antiepileptic drug oxcar bazepine (OXC). The purpose of this study was to define the metabolic pathw ay especially in terms of stereoselectivity, and to estimate the possibilit y 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 acti vity. In addition, incubations with liver microsomes from these three speci es plus dog and monkey were compared to results obtained with human liver m icrosomes. 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 signif icant 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 equa l 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 corres ponding 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 ov er OXC since they most likely exhibit a 'cleaner' metabolism. From a therap eutic 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. (C) 2001 Elsevier Science B.V. All rights reserved.