Development and validation of a HPLC-UV method for 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in humans

Providing in vivo evidence of CYP3A4-mediated CPHP formation

Ji-Young Park, Jae Gook Shin

Research output: Contribution to journalArticle

Abstract

We developed a high-performance liquid chromatographic procedure for the determination of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in human. Chromatographic analysis was performed on a reverse-phase C18 column with a mobile phase containing 50 mM potassium phosphate buffer/acetonitrile (75: 25, vol/vol) using UV detection with a wavelength of 220 nm. The limits of detection for CPHP were 1 ng/ml in urine and the assay was linear over the concentration range of 2-500 ng/ml for urine. This analytical method was applied to measure CPHP in human. Nineteen healthy subjects were enrolled and all subjects received a single oral dose of 5 mg haloperidol following a treatment of placebo or itraconazole at 200 mg/day for 10 days in a randomized crossover manner. CPHP was detected in urine samples and average recovered amount of CPHP was 81.31 µg/24 hr in the placebo phase and it was significantly reduced to 30.34 µg/24 hr after itraconazole treatment. The finding provides in vivo evidence that CPHP is an in vivo metabolite of haloperidol in human and its formation is mediated by CYP3A4.

Original languageEnglish
Pages (from-to)147-151
Number of pages5
JournalTranslational and Clinical Pharmacology
Volume24
Issue number3
DOIs
Publication statusPublished - 2016 Jan 1

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Cytochrome P-450 CYP3A
Poisons
Haloperidol
High Pressure Liquid Chromatography
Itraconazole
Urine
Placebos
Limit of Detection
4-(4'-chlorophenyl)-4-piperidinol
Chromatography
Healthy Volunteers
Buffers
Therapeutics

Keywords

  • CPHP
  • CYP3A4
  • Haloperidol
  • HPLC

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

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abstract = "We developed a high-performance liquid chromatographic procedure for the determination of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in human. Chromatographic analysis was performed on a reverse-phase C18 column with a mobile phase containing 50 mM potassium phosphate buffer/acetonitrile (75: 25, vol/vol) using UV detection with a wavelength of 220 nm. The limits of detection for CPHP were 1 ng/ml in urine and the assay was linear over the concentration range of 2-500 ng/ml for urine. This analytical method was applied to measure CPHP in human. Nineteen healthy subjects were enrolled and all subjects received a single oral dose of 5 mg haloperidol following a treatment of placebo or itraconazole at 200 mg/day for 10 days in a randomized crossover manner. CPHP was detected in urine samples and average recovered amount of CPHP was 81.31 µg/24 hr in the placebo phase and it was significantly reduced to 30.34 µg/24 hr after itraconazole treatment. The finding provides in vivo evidence that CPHP is an in vivo metabolite of haloperidol in human and its formation is mediated by CYP3A4.",
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