Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6

@article{Young2004EffectOQ,
  title={Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6},
  author={David Young and Kamal K. Midha and Michael J. Fossler and Edward M. Hawes and John W. Hubbard and G. Mckay and Elarien D. Korchinski},
  journal={European Journal of Clinical Pharmacology},
  year={2004},
  volume={44},
  pages={433-438}
}
SummaryHaloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to determine if this reversible metabolic pathway is linked to the debrisoquine 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… 
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TLDR
Evidence is presented to suggest that the sparteine/debrisoquine metabolizing isoenzyme P450IID6 contributes to this oxidation of haloperidol to RHAL in human livers and that both compounds compete for the same binding site.
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TLDR
In the extensive metabolizer phenotype it was demonstrated in one study that enzyme inhibition of quinidine was selective in terms of the metabolic pathways inhibited as well as stereoselective with respect to the inhibitor.
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The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.
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TLDR
The plasma levels of the reduced metabolite of haloperidol, after a single 2- or 4-mg oral dose of the parent drug, are significantly higher in PM than in EM of debrisoquine.
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TLDR
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TLDR
Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL.
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TLDR
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