title: Interaction of nefopam and orphenadrine with the cytochrome P-450 and the glutathione system in rat liver.
abstract: Nefopam, a cyclic analogue of orphenadrine, exhibits a type I (substrate) and a type II (ligand) interaction with ferri-cytochrome P-450 in control and phenobarbitone induced rat hepatic microsomes respectively. In-vitro metabolism of nefopam in phenobarbitone-induced microsomes leads to the production of a reactive metabolite which complexes with cytochrome P-450. In contrast to the known complexation of orphenadrine, complexation by nefopam can be inhibited by glutathione (GSH, 0.1-1.0 mM). However, in-vivo administration of nefopam to rats does not diminish the GSH content of liver cytosol nor increase oxidized glutathione levels nor alter the activities of GSH transferase and GSH peroxidase. In-vivo administration does not lead to cytochrome P-450 induction nor cytochrome P-450 complexation as has been shown for orphenadrine. Finally, nefopam inhibits the NADPH dependent endogenous H2O2 production in both control and phenobarbitone-induced microsomes.
authors.affiliation: Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: D
authors.initials: D
authors.lastname: Donnell
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
authors.forename: A
authors.initials: A
authors.lastname: Bast
mesh_terms: D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009340:Nefopam / Q000494:pharmacology*; D009966:Orphenadrine / Q000494:pharmacology*; D010079:Oxazocines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D010079:Oxazocines; D009340:Nefopam; D003577:Cytochrome P-450 Enzyme System; D009966:Orphenadrine; D005979:Glutathione Peroxidase; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D005982:Glutathione Transferase; D005978:Glutathione