title: Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein.
abstract: Incubation of phencyclidine (PCP) with rabbit liver microsomes and Na14CN resulted in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC, this compound was identified as the alpha-aminonitrile [1-(1-phenylcyclohexyl)-2-cyanopiperidine] derivative of PCP by use of chemical-ionization and gas-chromatographic coupled electron-impact mass spectrometry. Synthetic alpha-aminonitrile exhibited identical chemical properties and comigrated in HPLC and GLC with the metabolism derived cyano adduct. Molecular identification of the adduct formed by cyanide trapping provided evidence for the formation of an iminium ion during PCP metabolism. Quantitative estimation by HPLC demonstrated that the alpha-aminonitrile accounted for over 50% of the PCP metabolized in 30 min by hepatic microsomes in vitro. Metabolism-dependent covalent binding of [3H]PCP to rabbit liver microsomal proteins was inhibited by cyanide ion in a concentration-dependent manner with an IC50 value of 57 microM. The concentrations of cyanide ion used in these experiments did not significantly inhibit the metabolism of PCP. These results support our suggestions that iminium ion formation may represent an important intermediary step in the metabolism of PCP and that such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D007097:Imines / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010622:Phencyclidine / Q000378:metabolism*; D011485:Protein Binding; D011817:Rabbits; D012966:Sodium Cyanide / Q000494:pharmacology
chemical_list: D007097:Imines; D010622:Phencyclidine; D012966:Sodium Cyanide