EFFECT OF QUINIDINE ON THE INTERCONVERSION KINETICS BETWEEN HALOPERIDOL AND REDUCED HALOPERIDOL IN HUMANS - IMPLICATIONS FOR THE INVOLVEMENT OF CYTOCHROME P450IID6

Haloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to d etermine if this reversible metabolic pathway is linked to the debriso quine 4-hydroxylase isozyme of cytochrome P-450 (P450IID6), HAL (5 mg) or RHAL (5 mg) was orally administered to healthy male volunteers in a randomized crossover design both with and without a prior (1 h) oral dose of quinidine (250 mg bisulfate), a potent inhibitor of this isoz yme. Thirteen volunteers, 11 extensive metabolizers, 2 poor metabolize rs, completed all four phases of the study. Plasma samples harvested o ver seven days were analysed for HAL and RHAL. An expression for the a pparent fractional availability of metabolite from the parent compound given (Fapp(p)m) was derived and was used to determine whether HAL or RHAL is the preferred metabolite, and whether quinidine co-administra tion alters Fapp for either compound. The AUC (0-t) for both HAL and R HAL were significantly greater following the administration of either compound with quinidine compared with AUC (0-t) values obtained in the absence of quinidine. The maximum plasma concentration (C(max)) of th e administered compound was also greater following the administration of quinidine. Quinidine had no effect on the half-lives of the adminis tered compounds. The Fapp for HAL and RHAL were not significantly affe cted by the administration of quinidine, indicating that the interconv ersion of HAL and RHAL is not linked to P450IID6. The Fapp of RHAL aft er administration of HAL was significantly greater than the Fapp of HA L after RHAL administration, indicating that RHAL is the preferred met abolic form. This difference was not affected by quinidine. It is conc luded that: 1) RHAL is the preferred form after administration of eith er compound and is not affected by quinidine, 2) the interconversion o f HAL and RHAL is not affected by quinidine, indicating that this reve rsible metabolic process is not linked to P450IID6 and 3) there is a s ignificant increase in the AUC (0-t) and C(max) values following quini dine co-administration with either HAL or RHAL. The precise mechanism of this interaction can not be established from this study, however, t he observed increases in AUC (0-t) and C(max) may be explained with a simple tissue blinding displacement mechanism.