Pharmacokinetics and metabolism of UK-383,367 in rats and dogs: a rationale for long-lived plasma radioactivity.
UK-383,367 (5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazole-3-carboxamide) is a novel procollagen C-proteinase inhibitor evaluated for the treatment of post-surgical dermal scarring. It is extensively metabolized in rat and dog absorption, distribution, metabolism and excretion studies, and a metabolic pathway for UK-383,367 was determined. A long-lived metabolite was identified in dog plasma. Data indicate that this metabolite results from the oxadiazole ring-cleavage-producing oxamic acid, oxamide and oxalic acid. Ion exclusion chromatography was used to identify these polar metabolites, which were unretained on a standard reversed-phase high-performance liquid chromatography system. The oxamide metabolite was identified as the long-lived radioactivity, which was observed in dog plasma.
Allan
G A
GA
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK. gill.allan@pfizer.com
Gedge
J I
JI
Nedderman
A N R
AN
Roffey
S J
SJ
Small
H F
HF
Webster
R
R
D000284:Administration, Oral; D000818:Animals; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002853:Chromatography, Liquid; D002921:Cicatrix / Q000188:drug therapy; D004285:Dogs; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D010949:Plasma; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011851:Radioactivity; D051381:Rats; D017207:Rats, Sprague-Dawley
D019485:Bone Morphogenetic Proteins; D010069:Oxadiazoles; D011480:Protease Inhibitors; C512732:UK-383,367; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; C525708:Bmp1 protein, rat; D055395:Bone Morphogenetic Protein 1