Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences.
Excretion and metabolism of zoniporide were investigated in humans after intravenous infusion of [(14)C]zoniporide at an 80-mg dose. Bile was the primary route of excretion because 57% of dose was recovered in the feces after intravenous infusion. Zoniporide was primarily cleared via metabolism in humans. 2-Oxozoniporide (M1) was the major excretory and circulating metabolite in humans and was catalyzed by aldehyde oxidase (K(m) of 3.4 microM and V(max) of 74 pmol/min/mg protein). Metabolites M2 (17% of the dose) and M3 (6.4% of circulating radioactivity), in which the guanidine moiety was hydrolyzed to a carboxylic acid, were also detected in human feces and plasma, respectively, suggesting that hydrolysis was another route of metabolism of zoniporide in humans. The metabolism and excretion of [(14)C]zoniporide in rats and dogs were also evaluated. As in humans, bile was the primary route of excretion of the radiolabeled material in both species, and metabolism was the primary route of clearance. A comparison of plasma metabolites showed that for M3, rats had a higher concentration than human or dog. M1 was absent in dog and present in human and rat plasma at comparable levels, whereas comparison of excreta showed that the total body burden of M1 was greater in rat than that in human. No further evaluation of M2 was considered because it was detected only in the human fecal extracts. Hence, no further toxicological evaluation of the three human metabolites was undertaken.
Dalvie
Deepak
D
Pfizer Global Research and Development, San Diego, California, USA. deepak.dalvie@pfizer.com
Zhang
Chenghong
C
Chen
Weichao
W
Smolarek
Teresa
T
Obach
R Scott
RS
Loi
Cho-Ming
CM
D000293:Adolescent; D000328:Adult; D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D001822:Body Burden; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006146:Guanidines / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism; D055815:Young Adult
D006146:Guanidines; D011720:Pyrazoles; C424422:zoniporide; D042931:Aldehyde Oxidase