RT Journal Article
SR Electronic
T1 Mechanism-based inhibition of cytochrome P-450 by heterocyclic analogues of phencyclidine.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 648
OP 652
VO 15
IS 5
A1 J F Brady
A1 J Dokko
A1 E W Di Stefano
A1 A K Cho
YR 1987
UL http://dmd.aspetjournals.org/content/15/5/648.abstract
AB Three homologues of 1-(1-phenylcyclohexyl)piperidine (PCP) containing the five-, six-, and seven-membered heterocyclic ring (1-(1-phenylcyclohexyl)pyrrolidine (PCPY), PCP, 1-(1-phenylcyclohexyl)hexamethyleneimine (PCHMI) were preincubated with microsomes from phenobarbital-induced rabbit liver. The microsomes were then diluted, an additional charge of NADPH was added, and N-demethylation of benzphetamine was determined. Preincubation of the microsomes with the analogues lowered P-450-dependent N-demethylation by a process that was NADPH-dependent, reduced CO binding to microsomes, and followed pseudo-first order kinetics. The relative rates of inactivation, PCP greater than or equal to PCPY greater than PCHMI, agreed with the order of inhibition of CO binding to reduced microsomes. This mechanism-based inhibition was not observed with phenylcyclohexylamine, indicating that the substituted nitrogen is necessary. The substituted nitrogen must also be part of a heterocyclic ring since the diethylamino analogue of PCP did not exhibit the same type of inhibition a heterocyclic ring is involved. These trends correlated with the expected relative stabilities of the cyclic form of the carbinolamine suggesting that the inhibitory species was formed from the closed ring isomer.