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In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol.
Eur J Clin Pharmacol. 1999 Oct; 55(8):599-604.EJ

Abstract

OBJECTIVE

To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL).

METHODS

The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied.

RESULTS

After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes.

CONCLUSION

The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence.

Authors+Show Affiliations

Pan L
Heymans Institute of Pharmacology, University of Gent Medical School, De Pintelaan 185, B-9000 Gent, Belgium.
Belpaire FM
No affiliation info available

MeSH

BiotransformationChildCytochrome P-450 CYP1A2Cytochrome P-450 CYP1A2 InhibitorsCytochrome P-450 CYP2D6Cytochrome P-450 CYP2D6 InhibitorsCytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDopamine AntagonistsEnzyme InhibitorsHaloperidolHumansIsoenzymesMicrosomes, LiverMiddle AgedMixed Function OxygenasesOxidation-ReductionTheophylline

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10541779

Citation

Pan, L, and F M. Belpaire. "In Vitro Study On the Involvement of CYP1A2, CYP2D6 and CYP3A4 in the Metabolism of Haloperidol and Reduced Haloperidol." European Journal of Clinical Pharmacology, vol. 55, no. 8, 1999, pp. 599-604.
Pan L, Belpaire FM. In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol. Eur J Clin Pharmacol. 1999;55(8):599-604.
Pan, L., & Belpaire, F. M. (1999). In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol. European Journal of Clinical Pharmacology, 55(8), 599-604.
Pan L, Belpaire FM. In Vitro Study On the Involvement of CYP1A2, CYP2D6 and CYP3A4 in the Metabolism of Haloperidol and Reduced Haloperidol. Eur J Clin Pharmacol. 1999;55(8):599-604. PubMed PMID: 10541779.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol. AU - Pan,L, AU - Belpaire,F M, PY - 1999/12/14/pubmed PY - 1999/12/14/medline PY - 1999/12/14/entrez SP - 599 EP - 604 JF - European journal of clinical pharmacology JO - Eur J Clin Pharmacol VL - 55 IS - 8 N2 - OBJECTIVE: To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL). METHODS: The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied. RESULTS: After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes. CONCLUSION: The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence. SN - 0031-6970 UR - https://www.unboundmedicine.com/medline/citation/10541779/In_vitro_study_on_the_involvement_of_CYP1A2_CYP2D6_and_CYP3A4_in_the_metabolism_of_haloperidol_and_reduced_haloperidol_ L2 - https://dx.doi.org/10.1007/s002280050679 DB - PRIME DP - Unbound Medicine ER -