Carbamazepine: a 'blind' assessment of CYP-associated metabolism and interactions in human liver-derived in vitro systems

1. The ability of various in vitro systems for CYP enzymes (computer modell ing, human liver microsomes, precision-cut liver slices, hepatocytes in cul ture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevan t human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its c hemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidatio n) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly pred icted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by t he addition of exogenous cytochrome-b(5), leading to a considerable over-pr ediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7-ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, a ll liver-derived systems provide useful information for prediction of metab olic routes, rates and interactions.