Leurs R, Donnell D, Timmerman H, Bast A
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
J Pharm Pharmacol. 1989 Jun;41(6):388-93. doi: 10.1111/j.2042-7158.1989.tb06483.x.
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.
奈福泮是奥芬那君的环状类似物，在正常和苯巴比妥诱导的大鼠肝微粒体中，它分别与高铁细胞色素P-450表现出I型（底物）和II型（配体）相互作用。在苯巴比妥诱导的微粒体中，奈福泮的体外代谢会产生一种与细胞色素P-450结合的活性代谢产物。与已知的奥芬那君络合情况不同，奈福泮的络合可被谷胱甘肽（GSH，0.1 - 1.0 mM）抑制。然而，给大鼠体内注射奈福泮并不会降低肝细胞溶质中的谷胱甘肽含量，也不会增加氧化型谷胱甘肽水平，也不会改变谷胱甘肽转移酶和谷胱甘肽过氧化物酶的活性。如奥芬那君所示，体内给药不会导致细胞色素P-450诱导或细胞色素P-450络合。最后，奈福泮在正常和苯巴比妥诱导的微粒体中均抑制NADPH依赖性内源性过氧化氢的产生。
