Phencyclidine iminium ion. NADPH-dependent metabolism, covalent binding to macromolecules, and inactivation of cytochrome(s) P-450

Drug Metab Dispos. 1987 Jul-Aug;15(4):485-90.


The phencyclidine iminium ion (PCP-Im+), a potentially reactive 2,3,4,5-tetrahydropyridinium species, is formed by the cytochrome(s) P-450-catalyzed alpha-carbon oxidation of phencyclidine (PCP), a commonly abused psychotomimetic agent. Incubation of PCP-Im+ with liver microsomes obtained from phenobarbital-induced rabbits resulted in over 50% loss of microsomal N-demethylase activity and 30% reduction in cytochrome(s) P-450 content. These effects were concentration-dependent, irreversible, and exhibited pseudo-first order kinetics, characteristics of a mechanism-based enzyme inactivation process. Incubation of 3H-PCP-Im+ with liver microsomes resulted in covalent binding of radioactive material to macromolecules by a process that also was NADPH-dependent. PCP-Im+ was metabolized by liver microsomes in the presence of NADPH and this metabolism was inhibited by SKF 525A and carbon monoxide. HPLC analysis has led to the preliminary characterization of an oxidized metabolite of PCP-Im+ which also is formed from PCP. These results support the proposal that this tetrahydropyridinium metabolite of PCP is biotransformed in a cytochrome(s) P-450-catalyzed reaction to form reactive species capable of covalent interactions with biomacromolecules.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biotransformation
  • Cytochrome P-450 Enzyme Inhibitors*
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / metabolism
  • NADP / pharmacology*
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Phencyclidine / metabolism*
  • Phencyclidine / pharmacology
  • Rabbits


  • Cytochrome P-450 Enzyme Inhibitors
  • NADP
  • Oxidoreductases, N-Demethylating
  • Phencyclidine