title: Diazepam metabolism by rat and human liver in vitro: inhibition by mephenytoin.
abstract: 1. Diazepam metabolism and its association with mephenytoin hydroxylase were studied in vitro using human and rat livers. 2. Enzyme kinetic parameters were obtained for the formation of p-hydroxydiazepam (p-hydroxy-DZP), N-desmethyldiazepam (NDZ), and temazepam (TMZ) from diazepam (DZP) in rat liver fractions. The Km values for formation in rat of p-hydroxy-DZP, NDZ and TMZ were 14 +/- 3 (SEM) microM, 44 +/- 4 and 63 +/- 8, respectively; clearance values calculated from Vmax/Km were 5.7, 3.2 and 4.9 ml/g per min, respectively. 3. Mephenytoin (MP) competitively inhibited, in rat liver, the formation of NDZ, but not the formation of p-hydroxy-DZP or TMZ; in human liver neither NDZ nor TMZ formation was inhibited by MP. 4. In seven different human livers the formation of p-hydroxy-DZP represented a minor pathway compared to the formation of NDZ and TMZ.
authors.affiliation: Department of Pharmacology, University of Toronto, Canada.
authors.forename: T V
authors.initials: TV
authors.lastname: Beischlag
authors.forename: W
authors.initials: W
authors.lastname: Kalow
authors.forename: W A
authors.initials: WA
authors.lastname: Mahon
authors.forename: T
authors.initials: T
authors.lastname: Inaba
mesh_terms: D000818:Animals; D002849:Chromatography, Gas; D003975:Diazepam / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008617:Mephenytoin / Q000494:pharmacology*; D008745:Methylation; D003708:Nordazepam / Q000378:metabolism / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic / Q000502:physiology; D051381:Rats; D013693:Temazepam / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D003708:Nordazepam; D013693:Temazepam; D003975:Diazepam; D008617:Mephenytoin