Pharmacokinetics of haloperidol: an update.

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Kudo S, Ishizaki T

Pharmacokinetics of haloperidol: an update.

Clin Pharmacokinet. 1999 Dec;37(6):435-56. doi: 10.2165/00003088-199937060-00001.

PubMed ID

10628896 [ View in PubMed

]

Abstract

Haloperidol is commonly used in the therapy of patients with acute and chronic schizophrenia. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine diphosphoglucose glucuronosyltransferase. The greatest proportion of the intrinsic hepatic clearance of haloperidol is by glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for the metabolism of haloperidol in humans. The intrinsic clearances of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude, suggesting that the same enzyme system is responsible for the 3 reactions. Large variation in the catalytic activity was observed in the CYP-mediated reactions, whereas there appeared to be only small variations in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and an inhibitor, as well as a stimulator, of CYP2D6. Reduced haloperidol is also a substrate of CYP3A4 and inhibitor of CYP2D6. Pharmacokinetic interactions occur between haloperidol and various drugs given concomitantly, for example, carbamazepine, phenytoin, phenobarbital, fluoxetine, fluvoxamine, nefazodone, venlafaxine, buspirone, alprazolam, rifampicin (rifampin), quinidine and carteolol. Overall, drug interaction studies have suggested that CYP3A4 is involved in the biotransformation of haloperidol in humans. Interactions of haloperidol with most drugs lead to only small changes in plasma haloperidol concentrations, suggesting that the interactions have little clinical significance. On the other hand, the coadministration of carbamazepine, phenytoin, phenobarbital, rifampicin or quinidine affects the pharmacokinetics of haloperidol to an extent that alterations in clinical consequences would be expected. In vivo pharmacogenetic studies have indicated that the metabolism and disposition of haloperidol may be regulated by genetically determined polymorphic CYP2D6 activity. However, these findings appear to contradict those from studies in vitro with human liver microsomes and from studies of drug interactions in vivo. Interethnic and pharmacogenetic differences in haloperidol metabolism may explain these observations.

DrugBank Data that Cites this Article

Drugs

Haloperidol

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Haloperidol	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Haloperidol	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
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Amitriptyline Haloperidol	The serum concentration of Amitriptyline can be increased when it is combined with Haloperidol.
Amitriptylinoxide Haloperidol	The serum concentration of Amitriptylinoxide can be increased when it is combined with Haloperidol.
Amoxapine Haloperidol	The serum concentration of Amoxapine can be increased when it is combined with Haloperidol.
Butriptyline Haloperidol	The serum concentration of Butriptyline can be increased when it is combined with Haloperidol.
Clomipramine Haloperidol	The serum concentration of Clomipramine can be increased when it is combined with Haloperidol.