Biotransformation of phencyclidine.

Abstract

PCP is metabolized extensively in the body via a variety of metabolic routes. Biotransformation is a major mechanism of PCP elimination in humans and termination of PCP action in mice. In general, PCP metabolites are less active pharmacologically than PCP itself. Primary metabolism involves hydroxylation of the alicyclic rings at several carbon atoms by cytochrome P-450-mediated monooxygenase. Hydroxylation of the aromatic ring seems to be less likely and has not been conclusively demonstrated. Hydroxylation of PCP at carbon 2 of the piperidine ring to form the unstable carbinolamine leads to formation of a series of polar, open-ring compounds. Monohydroxylated metabolites are conjugated with glucuronic or sulfuric acid, or are further hydroxylated to dihydroxy derivatives that can also be subject to conjugation. Formation of highly reactive electrophilic metabolites of PCP have been demonstrated in vitro in microsomal preparations. Covalent modification of tissue macromolecules by reactive intermediates can be responsible for suicide inactivation of cytochrome P-450 and can possibly mediate some long-term toxic effects of PCP. PCP inhaled by cigarette smoking is metabolized via similar routes. About 50% of the PCP in cigarette smoke is converted to PC, a major product of thermal degradation of PCP. PC and its hydroxylated and conjugated metabolites appear to contribute little to the pharmacology or acute toxicity of PCP.