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Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol.
Br J Clin Pharmacol. 1997 Dec; 44(6):557-64.BJ

Abstract

AIMS

The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N-dealkylation of haloperidol (HAL).

METHODS

In vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms. N-dealkylation of HAL was assessed by measuring the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP).

RESULTS

There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. Km and Vmax values ranged respectively from 50 to 78 microM and from 180 to 412 pmol mg-1 min-1 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 activity of dextromethorphan O-demethylase (CYP2D6), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (Ki=0.1 microM), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC50 > 100 microM). CPHP formation was, moreover, enhanced by apha-naphtoflavone, an effect common to CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited CPHP formation, whereas no inhibition was observed in the presence of CYP2D6 antibodies. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to CPHP formation rate, with no detectable effect of other CYP isoforms (CYP1A2, CYP2D6 and CYP2C9). HAL inhibited dextromethorphan O-demethylase (CYP2D6) with IC50 values between 2.7 and 8.5 microM, but not (IC50 > 100 microM) dextromethorphan N-demethylase (CYP3A4), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9).

CONCLUSIONS

These results strongly suggest that the N-dealkylation of HAL in human liver microsomal preparations is mediated by CYP3A4.

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Authors+Show Affiliations

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

MeSH

Antibodies, BlockingAntibodies, MonoclonalAntipsychotic AgentsCell LineChromatography, High Pressure LiquidCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemDealkylationEnzyme InductionHaloperidolHumansIn Vitro TechniquesIndicators and ReagentsIsoenzymesKineticsMicrosomes, Liver

Pub Type(s)

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

Language

eng

PubMed ID

9431831

Citation

Pan, L P., et al. "Characterization of the Cytochrome P450 Isoenzymes Involved in the in Vitro N-dealkylation of Haloperidol." British Journal of Clinical Pharmacology, vol. 44, no. 6, 1997, pp. 557-64.
Pan LP, Wijnant P, De Vriendt C, et al. Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. Br J Clin Pharmacol. 1997;44(6):557-64.
Pan, L. P., Wijnant, P., De Vriendt, C., Rosseel, M. T., & Belpaire, F. M. (1997). Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. British Journal of Clinical Pharmacology, 44(6), 557-64.
Pan LP, et al. Characterization of the Cytochrome P450 Isoenzymes Involved in the in Vitro N-dealkylation of Haloperidol. Br J Clin Pharmacol. 1997;44(6):557-64. PubMed PMID: 9431831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. AU - Pan,L P, AU - Wijnant,P, AU - De Vriendt,C, AU - Rosseel,M T, AU - Belpaire,F M, PY - 1998/2/12/pubmed PY - 1998/2/12/medline PY - 1998/2/12/entrez SP - 557 EP - 64 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 44 IS - 6 N2 - AIMS: The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N-dealkylation of haloperidol (HAL). METHODS: In vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms. N-dealkylation of HAL was assessed by measuring the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP). RESULTS: There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. Km and Vmax values ranged respectively from 50 to 78 microM and from 180 to 412 pmol mg-1 min-1 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 activity of dextromethorphan O-demethylase (CYP2D6), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (Ki=0.1 microM), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC50 > 100 microM). CPHP formation was, moreover, enhanced by apha-naphtoflavone, an effect common to CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited CPHP formation, whereas no inhibition was observed in the presence of CYP2D6 antibodies. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to CPHP formation rate, with no detectable effect of other CYP isoforms (CYP1A2, CYP2D6 and CYP2C9). HAL inhibited dextromethorphan O-demethylase (CYP2D6) with IC50 values between 2.7 and 8.5 microM, but not (IC50 > 100 microM) dextromethorphan N-demethylase (CYP3A4), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). CONCLUSIONS: These results strongly suggest that the N-dealkylation of HAL in human liver microsomal preparations is mediated by CYP3A4. SN - 0306-5251 UR - https://www.unboundmedicine.com/medline/citation/9431831/Characterization_of_the_cytochrome_P450_isoenzymes_involved_in_the_in_vitro_N_dealkylation_of_haloperidol_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=1997&volume=44&issue=6&spage=557 DB - PRIME DP - Unbound Medicine ER -