Metabolism of Phencyclidine by Human Liver Microsomes

• Published in: Drug metabolism and disposition Vol. 25; no. 5; pp. 557 - 563
• Main Authors: LAURENZANA, E. M, OWENS, S. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.05.1997
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Female; Hallucinogens - metabolism; Hallucinogens - pharmacology; Humans; Hydroxylation; In Vitro Techniques; Infant; Isoenzymes - metabolism; Male; Medical sciences; Microsomes, Liver - enzymology; Middle Aged; Neuropharmacology; Oxidoreductases, N-Demethylating - antagonists & inhibitors; Oxidoreductases, N-Demethylating - metabolism; Pharmacology. Drug treatments; Phencyclidine - metabolism; Phencyclidine - pharmacology; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Testosterone - metabolism; Troleandomycin - pharmacology; Human; Unspecific monooxygenase; Enzyme; Digestive system; Isozyme; Psychotropic; Cytochrome P450; Liver; Microsome; Metabolism; In vitro; Phencyclidine; Enzymatic activity; Anesthetic; Interindividual comparison; Hallucinogen; Piperidine derivatives; Drug-metabolizing enzyme; Oxidoreductases
• ISSN: 0090-9556; 1521-009X

These studies examined in vitro metabolism of phencyclidine (PCP) in a series of human liver microsomes ( N = 10). Each sample was characterized for cytochrome P 450 (CYP) content and for CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, CYP3A, CYP4A, and lauric acid 11-hydroxylation metabolic activities. At least five PCP metabolites ( c -PPC, t -PPC, PCHP, an unknown metabolite, and an irreversibly bound metabolite) were formed by the various human liver microsomes. Nevertheless, there was a large degree of inter-individual variation in the metabolite formation. For example, the irreversibly bound metabolite was formed in detectable amounts in only four of the ten samples. c -PPC, t -PPC and the irreversibly bound PCP metabolite formation rates significantly correlated with CYP3A activity. The CYP3A inhibitor troleandomycin was used to inhibit the formation of PCP metabolites. Troleandomycin inhibition was dose dependent with the highest dose producing complete inhibition of the formation of c -PPC, t -PPC, PCHP, and the irreversibly bound metabolite. In addition, PCP inhibited CYP3A-mediated testosterone 6β-hydroxylation by 50%. Furthermore, the relative intensity of CYP3A immunoreactive proteins significantly correlated with testosterone 6β-hydroxylation and with PCP metabolite formation (except for the unknown metabolite). PCHP formation also correlated with CYP1A activity, while the formation of the unknown PCP metabolite correlated with CYP2A activity. These studies suggest that several CYP isoforms contribute to PCP metabolism and that CYP3A plays a major role in PCP biotransformation in human liver microsomes.