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Rapid CommunicationShort Communication

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

Amit S. Kalgutkar, Timothy J. Taylor, Karthik Venkatakrishnan and Emre M. Isin
Drug Metabolism and Disposition March 2003, 31 (3) 243-249; DOI: https://doi.org/10.1124/dmd.31.3.243
Amit S. Kalgutkar
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Timothy J. Taylor
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Karthik Venkatakrishnan
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Emre M. Isin
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Abstract

As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP+) were assessed in human liver microsomes and heterologously expressed enzymes. Based on recent reports on drug-drug interactions between haloperidol and antidepressants including selective serotonin reuptake inhibitors, the inhibitory effects of antidepressants on the CYP3A4/5-mediated haloperidol bioactivation were also evaluated. HPP+ formation followed Michaelis-Menten kinetics in microsomes, recombinant CYP3A4, and CYP3A5 with Km values of 24.4 ± 8.9 μM, 18.3 ± 4.9 μM, and 200.2 ± 47.6 μM, respectively, andVmax values of 157.6 ± 13.2 pmol/min/mg of protein, 10.4 ± 0.6 pmol/min/pmol P450, and 5.16 ± 0.6 pmol/min/pmol P450, respectively. The similarity inKm values between human liver microsomal and recombinant CYP3A4 incubations suggests that polymorphic CYP3A5 may not be an important genetic contributor to the interindividual variability in CYP3A-mediated haloperidol clearance pathways. Besides HPP+, a novel 4-fluorophenyl-ring-hydroxylated metabolite of haloperidol in microsomes/CYP3A enzymes was also detected. Its formation was consistent with previous reports on the detection ofO-sulfate and -glucuronide conjugates of a fluorophenyl ring-hydroxylated metabolite of haloperidol in human urine. Finally, all antidepressants except buspirone inhibited the CYP3A4/5-catalyzed oxidation of haloperidol to HPP+ in a concentration-dependent manner. Based on the estimated IC50values for inhibition of HPP+ formation in microsomes, the antidepressants were ranked in the following order: fluoxetine, nefazodone, norfluoxetine, trazodone, and fluvoxamine. These inhibition results suggest that clinically observed drug-drug interactions between haloperidol and antidepressants may arise via the attenuation of CYP3A4/5-mediated 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol biotransformation pathways.

Footnotes

  • Abbreviations used are::
    HP
    haloperidol
    TD
    tardive dyskinesias
    CPHP
    4-(4-chlorophenyl)-4-hydroxypiperidine
    HPTP
    4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine
    HPP+
    4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium
    RHPP+
    4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-hydroxybutyl]-pyridinium
    MPP+
    1-methyl-4-phenylpyridinium
    P450
    cytochrome P450
    DMSO
    dimethyl sulfoxide
    SSRI
    selective serotonin reuptake inhibitor
    LC-MS/MS
    high performance liquid chromatography-tandem mass spectrometry
    HPLC
    high performance liquid chromatography
    Rt
    retention time
    CID
    collision-induced dissociation
    NPP†
    N-nonyl-4-phenylpyridinium
    • Received July 26, 2002.
    • Accepted November 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Rapid CommunicationShort Communication

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

Amit S. Kalgutkar, Timothy J. Taylor, Karthik Venkatakrishnan and Emre M. Isin
Drug Metabolism and Disposition March 1, 2003, 31 (3) 243-249; DOI: https://doi.org/10.1124/dmd.31.3.243

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Rapid CommunicationShort Communication

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

Amit S. Kalgutkar, Timothy J. Taylor, Karthik Venkatakrishnan and Emre M. Isin
Drug Metabolism and Disposition March 1, 2003, 31 (3) 243-249; DOI: https://doi.org/10.1124/dmd.31.3.243
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