METABOLISM OF PHENCYCLIDINE - THE ROLE OF IMINIUM ION FORMATION IN COVALENT BINDING TO RABBIT MICROSOMAL PROTEIN

Abstract

Incubation of phencyclidine (PCP) [a drug of abuse] with rabbit liver microsomes and Na14CN resutled in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC [high performance liquid chromatography], 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 > 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 CN- in a concentration-dependent manner with an IC50 [median inhibitory concentration] value of 57 .mu.M. The concentrations of CN- used in these experiments did not significantly inhibit PCP metabolism. Iminium ion formation may represent an important intermediary step in PCP metabolism and such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.