[The biotransformation of the anticonvulsant 4-p-chlorophenylpyrrol-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 small concentration are excreted in urine and faeces, six of them could be isolated and identified as quantitative dominating compounds. Compound 1 is attacked in different sites of the molecule by the cytochrome P-450 system. At the morphine ring N- and O-dealkylation reactions take place leading to the cleavage of the ring. After that a stepwise degradation by oxidative and reductive processes occurs. Further reactions 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 hepatocytes culture solely the two main metabolites are formed. Compound 1 is characterized by enzyme inducing activities. The oxidative demethylation of p-nitroanisole is increased 4-fold after pretreatment.
Langner
A
A
Fachbereich Pharmazie der Humboldt-Universität zu Berlin.
Rätzer
J
J
Rickert
H
H
Nerlich
C
C
Franke
P
P
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005243:Feces / Q000737:chemistry; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009025:Morpholines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet
D000927:Anticonvulsants; D009025:Morpholines; D011758:Pyrroles; D003577:Cytochrome P-450 Enzyme System; C085562:AWD 140076
Untersuchungen zur Biotransformation des Antikonvulsivums 4-p-Chlorophenylpyrrol-3-morpholino-2-carbonsäuremethylester (AWD 140-076).