Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]- 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride, a gamma-aminobutyric acid uptake inhibitor.
Single-dose administration of 50 mg of 1-[2-[bis[4- (trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid monohydrochloride resulted in temporary neurological and psychological symptoms in two subjects. Because of the nature of adverse effects, urine from a subject who received CI-966 orally was extracted to investigate the metabolism of CI-966 in man. An unknown urinary component was identified as a pyridinium metabolite of CI-966 based on HPLC-MS and 1H and 19F NMR. Structural confirmation was achieved by chromatographic and spectroscopic comparisons to a reference standard. In several in vitro screens and preclinical studies, the pyridinium metabolite appears to possess minimal pharmacological activity.
Radulovic
L
L
Pharmacokinetics and Drug Metabolism, Department Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105.
Woolf
T
T
Bjorge
S
S
Taylor
C
C
Reily
M
M
Bockbrader
H
H
Chang
T
T
D000284:Administration, Oral; D004334:Drug Administration Schedule; D018756:GABA Antagonists; D006801:Humans; D008297:Male; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011726:Pyridinium Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000652:urine*
D018756:GABA Antagonists; D011725:Pyridines; D011726:Pyridinium Compounds; C067012:CI 966