Metabolism and pharmacokinetics of nufenoxole in animals and humans: an example of stereospecific hydroxylation of an isoquinuclidine ring

Abstract

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 (t_1/2 of 1.8 h) and monkey (t_1/2 of 4.9 h) compared with human (t_1/2 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.