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 h aloperidol (HP). Oxidative N-dealkylation, the major metabolic pathway of U p, gives rise to 3-(4-fluorobenzoyl)propionic acid (p-FBPA). Subsequent bet a-oxidation of p-FBPA produces p-fluorophenylacetic acid (p-FPA). The prese nce of p-FPA argues for the formation also of p-fluorophenylglyoxylic acid (p-FPGA) derived from beta-oxidation of p-FBPA. Plasma aminotransferases sh ould convert p-FPGA to p-FPG. The presence of p-FPG in these animals sugges t the presence of phenylglycine aminotransferases in the baboon and possibl y also in other primates, including the human. Reports by other authors fou nd that treatment with alpha-phenylglycine (alpha-PG), an "unnatural" amino acid, leads to striatal dopamine (DA) depletion in rabbits - an effect exp lained on the basis of alpha-PG competing with DA for the neuronal vesicula r storage sites. We performed in vitro DA release assays in mouse striatal synaptosomal preparations but found that neither alpha-PG nor p-FPG release d 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.