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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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Figure 2.
Representative chromatogram of urine samples spiked with 100 ng/ml of CPHP and internal standard (A) of blank urine samples, no spiked blank urine samples (B), and collected urine sample from a healthy subject who administered with 5 mg of haloperidol (C). The labeled chromatographic peaks indicate CPHP (I) and the internal standard metoprolol (II), respectively.
Figure 3.
Comparison of urinary CPHP recovery in the placebo and itraconazole phases after a single oral administration of 5 mg haloperidol in 19 healthy male subjects.
Table 1.
Extraction recovery for the assay of CPHP in urine samples (n=4)
| CPHP Concentration (ng/ml) | Recovery rate (%) |
|---|---|
| 5 | 82.6 ± 5.7 |
| 50 | 87.6 ± 9.4 |
| 500 | 90.4 ± 6.5 |
Table 2.
Intra-day and inter-day precision and accuracy of CPHP in urine samples
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