Metabolism and disposition of a potent and selective GABA-Aalpha2/3 receptor agonist in healthy male volunteers.
[14C]7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine ([14C]-TPA023; 99 microCi/dose) was administered to five young, healthy, fasted male subjects as a single oral dose (3.0 mg) in solution (propylene glycol/water, 10:90 v/v). The parent compound was rapidly absorbed (plasma Tmax approximately 2 h), exhibited an apparent terminal half-life of 6.7 h, and accounted for approximately 53% of the total radioactivity in plasma. After 7 days of collection, the mean total recovery of radioactivity in the excreta was 82.6%, with 53.2% and 29.4% in urine and feces, respectively. Radiochromatographic analysis of the excreta revealed that TPA023 was metabolized extensively, and only trace amounts of unchanged parent were recovered. Radiochromatograms of urine and feces showed that TPA023 underwent metabolism via three pathways (t-butyl hydroxylation, N-deethylation, and direct N-glucuronidation). The products of t-butyl hydroxylation and N-deethylation, together with their corresponding secondary metabolites, accounted for the majority of the radioactivity in the excreta. In addition, approximately 10.3% of the dose was recovered in urine as the triazolo-pyridazine N1-glucuronide of TPA023. The t-butyl hydroxy and N-desethyl metabolites of TPA023, the TPA023 N1-glucuronide, and the triazolo-pyridazine N1-glucuronide of N-desethyl TPA023 were present in plasma. In healthy male subjects, therefore, TPA023 is well absorbed and is metabolized extensively (t-butyl hydroxylation and N-deethylation > glucuronidation), and the metabolites are excreted in urine and feces.
Polsky-Fisher
Stacey L
SL
Department of Drug Metabolism, WP75B-200, Merck Research Laboratories, West Point PA 19486, USA. stacey_polsky@merck.com
Vickers
Stanley
S
Cui
Donghui
D
Subramanian
Raju
R
Arison
Byron H
BH
Agrawal
Nancy G B
NG
Goel
Thanh V
TV
Vessey
Laura K
LK
Murphy
M Gail
MG
Lasseter
Kenneth C
KC
Simpson
Richard C
RC
Vega
Jose M
JM
Rodrigues
A David
AD
D000284:Administration, Oral; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D005243:Feces / Q000737:chemistry; D058785:GABA-A Receptor Agonists; D020719:Glucuronides / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011963:Receptors, GABA-A; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D014151:Anti-Anxiety Agents; D002250:Carbon Radioisotopes; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; D020719:Glucuronides; D011724:Pyridazines; D011963:Receptors, GABA-A; D014230:Triazoles