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In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol.
Pharmacogenetics. 1998 Oct; 8(5):383-9.P

Abstract

In-vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms to identify the cytochrome P450 isoenzyme(s) involved in the back oxidation and N-dealkylation of reduced haloperidol. Back oxidation and N-dealkylation of reduced haloperidol were assessed by measuring the formation of haloperidol and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), respectively. The haloperidol and CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. For haloperidol formation Km values ranged from 51-59 microM, and Vmax values from 190-334 pmol mg(-1) min(-1); for CPHP formation Km values were 44-49 microM, and Vmax values 74-110 pmol mg(-1) min(-1). Haloperidol and CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N-demethylase activity (a marker of CYP3A4 activity), but not with the CYP2D6, CYP1A2 and CYP2C9 activity. Ketoconazole and troleandomycin, inhibitors of CYP3A4, inhibited competitively both haloperidol and CPHP formation, with a Ki value lower than 0.2 microM for ketoconazole and lower than 0.3 microM for troleandomycin. Sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine and paroxetine (CYP2D6) gave only little inhibition (IC50 > 60 microM). CPHP and haloperidol formation were, moreover, enhanced by alpha-naphthoflavone, an effect known for CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited haloperidol and CPHP formation, whereas CYP2D6 antibodies did not. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to haloperidol and CPHP formation rates, with no detectable effect of CYP1A2, CYP2D6 and CYP2C9. These results strongly suggest that back oxidation and N-dealkylation of reduced haloperidol in human liver microsomal preparations are mediated by CYP3A4.

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Authors+Show Affiliations

Pan LP
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
De Vriendt C
No affiliation info available
Belpaire FM
No affiliation info available

MeSH

AdolescentAdultAgedChildCytochrome P-450 CYP2D6 InhibitorsCytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDealkylationHaloperidolHumansIsoenzymesMicrosomes, LiverMiddle AgedMixed Function OxygenasesOxidation-ReductionPiperidines

Pub Type(s)

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

Language

eng

PubMed ID

9825830

Citation

Pan, L P., et al. "In-vitro Characterization of the Cytochrome P450 Isoenzymes Involved in the Back Oxidation and N-dealkylation of Reduced Haloperidol." Pharmacogenetics, vol. 8, no. 5, 1998, pp. 383-9.
Pan LP, De Vriendt C, Belpaire FM. In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics. 1998;8(5):383-9.
Pan, L. P., De Vriendt, C., & Belpaire, F. M. (1998). In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics, 8(5), 383-9.
Pan LP, De Vriendt C, Belpaire FM. In-vitro Characterization of the Cytochrome P450 Isoenzymes Involved in the Back Oxidation and N-dealkylation of Reduced Haloperidol. Pharmacogenetics. 1998;8(5):383-9. PubMed PMID: 9825830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. AU - Pan,L P, AU - De Vriendt,C, AU - Belpaire,F M, PY - 1998/11/24/pubmed PY - 1998/11/24/medline PY - 1998/11/24/entrez SP - 383 EP - 9 JF - Pharmacogenetics JO - Pharmacogenetics VL - 8 IS - 5 N2 - In-vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms to identify the cytochrome P450 isoenzyme(s) involved in the back oxidation and N-dealkylation of reduced haloperidol. Back oxidation and N-dealkylation of reduced haloperidol were assessed by measuring the formation of haloperidol and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), respectively. The haloperidol and CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. For haloperidol formation Km values ranged from 51-59 microM, and Vmax values from 190-334 pmol mg(-1) min(-1); for CPHP formation Km values were 44-49 microM, and Vmax values 74-110 pmol mg(-1) min(-1). Haloperidol and CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N-demethylase activity (a marker of CYP3A4 activity), but not with the CYP2D6, CYP1A2 and CYP2C9 activity. Ketoconazole and troleandomycin, inhibitors of CYP3A4, inhibited competitively both haloperidol and CPHP formation, with a Ki value lower than 0.2 microM for ketoconazole and lower than 0.3 microM for troleandomycin. Sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine and paroxetine (CYP2D6) gave only little inhibition (IC50 > 60 microM). CPHP and haloperidol formation were, moreover, enhanced by alpha-naphthoflavone, an effect known for CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited haloperidol and CPHP formation, whereas CYP2D6 antibodies did not. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to haloperidol and CPHP formation rates, with no detectable effect of CYP1A2, CYP2D6 and CYP2C9. These results strongly suggest that back oxidation and N-dealkylation of reduced haloperidol in human liver microsomal preparations are mediated by CYP3A4. SN - 0960-314X UR - https://www.unboundmedicine.com/medline/citation/9825830/In_vitro_characterization_of_the_cytochrome_P450_isoenzymes_involved_in_the_back_oxidation_and_N_dealkylation_of_reduced_haloperidol_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=9825830.ui DB - PRIME DP - Unbound Medicine ER -