On the metabolism of haloperidol

Abstract

1. p-Fluorobenzoyl-propionic acid, 4-(4-chlorophenyl)-4-hydroxy-piperidine, and reduced haloperidol were confirmed as metabolites of haloperidol. Their formation was catalysed by hepatic microsomes and was NADPH dependent.

2. The pyridinium metabolite of haloperidol (HP⁺) was identified. It is proposed that haloperidol first undergoes dehydration to form its 1,2,3,6-tetrahydropyridine analogue (HTP). HTP is then further metabolized to HP⁺, HTP N-oxide and its N-dealkylated product, 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP). HTP N-oxide was metabolized to CPTP and HTP. All these metabolites were confirmed by comparison with synthesized compounds using h.p.l.c. and h.p.l.c.-mass spectrometry.

3. Three unknown metabolites were present in microsomal metabolic incubations of haloperidol. One of them was tentatively characterized by h.p.l.c.-mass spectrometry as an oxygenated product of haloperidol, another appears to be the 2-pyridone analogue of haloperidol. The third metabolite was shown to be a neutral compound of unknown structure, which was not haloperidol N-oxide nor 4-hydroxy-4′-fluorobutyrophenone. In addition, HTP was metabolized to a further unknown product with a similar u.v. spectrum to that of HTP.

4. The identification of these metabolites led to the hypothesis that the metabolism of haloperidol is similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and may therefore produce motor neurone toxicity by a similar mechanism.