Intestinal metabolism of mephentermine and its biliary metabolites in male Wistar rats

Abstract

1. Intestinal metabolites produced in the incubation (0–24 h) of mephentermine (MP), phentermine (Ph), N-hydroxymephentermine (N-hydroxy-MP), N-hydroxyphentermine (N-hydroxy-Ph), p-hydroxymephentermine (p-hydroxy-MP) and p-hydroxyphentermine (p-hydroxy-Ph) with male Wistar rat intestinal contents under N₂ were examined by g.l.c. and g.l.c.-electron impact (EI) mass spectrometry. Metabolites produced in the anaerobic incubation of bile from rats given MP, with the intestinal contents were also examined. In addition, urinary and biliary metabolites of p-hydroxy-MP and p-hydroxy-Ph dosed orally to rat were examined.

2. Metabolites in the anaerobic incubation of N-hydroxy-MP and N-hydroxy-Ph were MP and Ph, and Ph, respectively. No metabolites were detected in the incubation of MP, Ph, p-hydroxy-MP and p-hydroxy-Ph.

3. p-Hydroxy-MP and p-hydroxy-Ph (major), and MP and Ph (minor) were detected when bile from rats given MP was incubated with intestinal contents.

4. Unchanged p-hydroxy-MP, and conjugates of p-hydroxy-MP and p-hydroxy-Ph, were detected in the 24-h urine of rats dosed with p-hydroxy-MP, which accounted for about 3, 72 and 1% dose, respectively. Unchanged p-hydroxy-Ph and conjugated p-hydroxy-Ph were detected in the 24-h urine of rats dosed with p-hydroxy-Ph, which accounted for about 4 and 68% dose, respectively.

5. Conjugated p-hydroxy-MP and conjugated p-hydroxy-Ph, which accounted for about 3% doses, were detected in the 24-h bile of rats dosed with p-hydroxy-MP and p-hydroxy-Ph.

6. Urinary and biliary conjugates of p-hydroxy-MP and p-hydroxy-Ph were considered to be glucuronides because of the inhibitory effect of saccharic acid 1,4-lactone (saccharolactone) on their hydrolysis with β-giucuronidase. This result, together with previous findings, shows that enterohepatic circulation of p-hydroxy-MP and p-hydroxy-Ph occurs in the metabolism of MP.