Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation.

Article Details

Citation

Copy to clipboard

Kudo S, Odomi M

Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation.

Eur J Clin Pharmacol. 1998 May;54(3):253-9.

PubMed ID

9681669 [ View in PubMed

]

Abstract

OBJECTIVE: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/- cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. RESULTS: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 micromol x l(-1), and the Vmax was 4.87 pmol x min(-1) x pmol(-1) P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k(i) value of 24.9 and 1390 micromol x l(-1), respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k(i) value of 4.3 micromol x l(-1). Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 micromol x l(-1), whereas higher concentrations of the compound (> 10 micromol x l(-1)) inhibited the hydroxylase activity. CONCLUSION: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Carteolol	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
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.