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Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia
Author(s) -
Eyles Darryl W,
McLennan Holly R,
Jones Alun,
McGrath John J,
Stedman Terry J,
Pond Susan M
Publication year - 1994
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1994.172
Subject(s) - haloperidol , metabolite , chemistry , urine , pyridinium , high performance liquid chromatography , excretion , blood plasma , pharmacokinetics , chromatography , endocrinology , pharmacology , medicine , biochemistry , dopamine , medicinal chemistry
Objective A pyridinium metabolite (HPP + ) of the neuroleptic drug haloperidol has been identified in rats and in the urine of patients. The purpose of this study was to measure the steady‐state blood and plasma concentrations and daily urinary excretion of HPP + in patients treated with haloperidol. Methods HPP + was measured by HPLC with fluorescence detection. The chromatograms also revealed the presence of a previously unknown pyridinium species, which was identified in urine by liquid chromatography/mass spectrometry/mass spectrometry as 4‐(4‐chlorophenyl)‐1‐4‐(4‐fluorophenyl)‐4‐hydroxybutylpyridinium (RHPP + ). Concentrations of RHPP + were then measured by HPLC. Results The steady‐state concentrations of HPP + or RHPP + in blood and plasma from 34 patients were virtually identical. The plasma concentrations of each metabolite were related to the daily dose of haloperidol and to its plasma concentrations. Nonlinearity in the elimination of RHPP + was suggested by the increase in the ratio between RHPP + and HPP + plasma concentrations with dose or steady‐state concentrations of haloperidol. The concentrations of RHPP + in plasma and urine generally exceeded those of HPP + ; the ratio between them in plasma ranged from 0.9 to 14.1. The daily urinary excretion of HPP + and RHPP + accounted for 0.40% ± 0.18% and 2.3% ± 1.4% of the haloperidol dose, respectively. The renal clearance of each species was 4.5 ± 2.5 and 11.3 ± 5.3 L/hr, respectively. Conclusions The presence of these pyridinium species in humans raises the concern that they may be neurotoxic in a manner similar to the dopaminergic pro‐neurotoxin, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Clinical Pharmacology and Therapeutics (1994) 56, 512–520; doi: 10.1038/clpt.1994.172