Metabolism and pharmacokinetics of nufenoxole in animals and humans: an example of stereospecific hydroxylation of an isoquinuclidine ring.
1. Nufenoxole, a novel antidiarrhoeal agent, was well absorbed in rat, monkey and human after oral administration. Systemic availability of nufenoxole was 85% in monkey and 102% in man. 2. The elimination rate was much faster in rat (t1/2 of 1.8 h) and monkey (t1/2 of 4.9 h) compared with human (t1/2 of 35.8 h). 3. After oral and i.v. 14C-nufenoxole, concentrations of 14C in human erythrocytes and saliva were approx. 3- and 4-fold lower, respectively, than plasma concentrations. 4. Nufenoxole was metabolized to metabolites hydroxylated on the methyl substituent and isoquinuclidine ring in rat and monkey. The isoquinuclidine ring hydroxylation, a major pathway in human, was stereospecific. 5. Following oral doses of 14C-nufenoxole the urinary excretion of radioactivity (about 8%) was less than the faecal excretion (66.6%) in rat, while urinary excretion was the major route of drug elimination (about 60%) in man. In monkey, urinary and faecal excretion were equally important.
Cook
C S
CS
Department of Drug Metabolism, G. D. Searle & Co., Skokie, IL 60077.
Campion
J G
JG
Hribar
J D
JD
Karim
A
A
D000328:Adult; D000818:Animals; D000930:Antidiarrheals / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008253:Macaca mulatta; D008297:Male; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism
D000930:Antidiarrheals; D010069:Oxadiazoles; C015627:nufenoxole