Urinary metabolites of pinacidil. II. Species difference in the metabolism of pinacidil.

1. Pinacidil was given orally to rabbit (10 mg/kg), dog (10 mg/kg), monkey (10 mg/kg) and mouse (150 mg/kg), the urinary metabolites were separated by h.p.l.c. and their structures determined by mass spectrometry. 2. Three new metabolites, namely, omega-hydroxy-pinacidil-O-glucuronide (M-8), pinacidil-pyridine-N-oxide-O-glucuronide (M-9) and pinacidil-pyridine-N-glucuronide (M-10) were isolated from rabbit urine, and one new metabolite, namely, pinacidil-pyridine-phenolic-glucuronide (M-11) was isolated from mouse urine. 3. M-9 is a unique glucuronide because the glucuronic acid is linked to the oxygen of pyridine-N-oxide. 4. In man, similar to rat, dog and mouse, pinacidil-pyridine-N-oxide (M-1) was the main urinary metabolite, with pyridine-N-oxidation being the major metabolic pathway. On the other hand, M-8 and M-9 were the most abundant metabolites in monkey and rabbit urine, respectively. Therefore, rat, dog and mouse have similar metabolism of pinacidil to man, but monkey and rabbit are significantly different in their metabolism of the drug.