INVESTIGATIONS ON THE BIOTRANSFORMATION O F THE ANTICONVULSANT 4-P-CHLOROPHENYLPYRROLE-3-MORPHOLINO-2-CARBOXYLIC ACID METHYL-ESTER (AWD-140-076)

4-p-Chlorphenylpyrrole-3-morpholino-2-carboxylic acid methylester (1; AWD 140-076) is a substance with anticonvulsive properties. After p.o. administration in male wistar rats many metabolites in relatively sma ll concentration are excreted in urine and faeces, six of them could b e isolated and identified as quantitative dominating compounds. Compou nd 1 is attacked in different sites of the molecule by the cytochrome P-450 system. At the morpholine ring N- and O-dealkylation reactions t ake place leading to the cleavage of the ring. After that a stepwise d egradation by oxidative and reductive processes occurs. Further reacti ons concern the N-oxidation of the morpholine nitrogen as well as the hydroxylation of the pyrrole skeleton forming the main metabolites. 5 metabolites are also present as sulfate or glucuronide conjugates. The quantity ratio of the phase I to phase II metabolites amounts to 9:1. In the in vitro test system isolated perfused rat liver and rat hepat ocytes culture solely the two main metabolites are formed. Compound 1 is characterized by enzyme inducing activities. The oxidative demethyl ation of p-nitroanisole is increased 4fold after pretreatment.