Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridinium species in the baboon.
The in vivo metabolic fate of haloperidol (HP) and its tetrahydropyridine analog HPTP have been examined in the baboon to investigate the formation of potentially neurotoxic pyridinium metabolites that have been observed previously in humans. Urine samples collected from baboons treated with HPTP were shown to contain, in addition to the parent drug, the corresponding reduced HPTP (RHPTP), generated by reduction of the butyrophenone carbonyl group. RHPTP was characterized by comparison with a synthetic standard using HPLC with electrochemical detection and HPLC/MS/MS. Another compound identified by LC/MS/MS was a glucuronide metabolite of RHPTP. The HP pyridinium (HPP+) and reduced pyridinium (RHPP+) metabolites were shown to be present in urine from both HP and HPTP treated baboons by HPLC using fluorescence detection. The urinary excretion profile of HPP+ and RHPP+ in both groups was essentially identical and, in contrast to that observed in rodents, closely paralleled the profile found in humans treated with HP. These data in the baboon suggest that the metabolic processes involved in the production of the pyridinium metabolites of HP are similar to those in humans. Furthermore, the HPTP-treated baboon may be an appropriate model in which to study the role of pyridinium metabolites in the induction of tardive dyskinesia.
Dept of Medicine, Univ of Queensland, Princess Alexandra Hospital, Brisbane, Australia. kavent@gpo.pa.uq.edu.au
K M
KM
Avent
E
E
Usuki
D W
DW
Eyles
R
R
Keeve
C J
CJ
Van der Schyf
N
N
Castagnoli
S M
SM
Pond
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D006220:Haloperidol / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D010215:Papio; D013050:Spectrometry, Fluorescence
D006220:Haloperidol