title: Cytochrome P-450 metabolic-intermediate complex formation with a series of diphenhydramine analogues.
abstract: A series of diphenhydramine analogues have been studied with regard to their formation of a metabolic intermediate (MI) during their biotransformation in phenobarbital induced rat hepatic microsomes. The MI forms a complex with reduced cytochrome P-450. MI complexation of cytochrome P-450 may result in drug-drug interactions and/or in cumulation of the parent compound. The extent of MI complex formation could be correlated with the lipophilicity of the substrates in a parabolic manner. A hydrophobic pocket of limited dimensions in cytochrome P-450 for the N-alkyl substituent of the substrates can be assumed. Moreover our data indicate a role for the O-atom in the diphenhydramine analogues for the interaction with cytochrome P-450.
authors.affiliation: Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Bast
authors.forename: A J
authors.initials: AJ
authors.lastname: Valk
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004155:Diphenhydramine / Q000031:analogs & derivatives / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
chemical_list: D004155:Diphenhydramine; D003577:Cytochrome P-450 Enzyme System