p-Fluorophenylglycine in the urine of baboons treated with HPTP, the tetrahydropyridine analog of haloperidol.
We report the presence of p-fluorophenylglycine (p-FPG) in the urine of six baboons treated with HPTP, the tetrahydropyridine dehydration product of haloperidol (HP). Oxidative N-dealkylation, the major metabolic pathway of HP, gives rise to 3-(4-fluorobenzoyl)propionic acid (p-FBPA). Subsequent beta-oxidation of p-FBPA produces p-fluorophenylacetic acid (p-FPA). The presence of p-FPA argues for the formation also of p-fluorophenylglyoxylic acid (p-FPGA) derived from beta-oxidation of p-FBPA. Plasma aminotransferases should convert p-FPGA to p-FPG. The presence of p-FPG in these animals suggest the presence of phenylglycine aminotransferases in the baboon and possibly also in other primates, including the human. Reports by other authors found that treatment with alpha-phenylglycine (alpha-PG), an "unnatural" amino acid, leads to striatal dopamine (DA) depletion in rabbits--an effect explained on the basis of alpha-PG competing with DA for the neuronal vesicular storage sites. We performed in vitro DA release assays in mouse striatal synaptosomal preparations but found that neither alpha-PG nor p-FPG released any DA. It therefore remains unclear whether p-FPG may be a contributing factor to neurologic side-effects such as tardive dyskinesia (TD) found in patients after long-term HP treatment.
Mienie
L J
LJ
Department of Biochemistry, Potchefstroom University for CHE, South Africa.
Bergh
J J
JJ
Bloomquist
J R
JR
Castagnoli
N
N
Steyn
S J
SJ
Van der Schyf
C J
CJ
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D004298:Dopamine / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000652:urine*; D006220:Haloperidol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D010215:Papio; D011422:Propionates / Q000378:metabolism
D014150:Antipsychotic Agents; D011422:Propionates; C080346:beta-(4-fluorobenzoyl)propionic acid; C101091:4(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)-1,2,3,6-tetrahydropyridine; C120979:4-fluorophenylglycine; D006220:Haloperidol; D005998:Glycine; D004298:Dopamine