Morphine 6-glucuronide: a metabolite of morphine with greater emetic potency than morphine in the ferret

Abstract

1. The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total retches and vomits for subcutaneous doses of 0.05 mg kg-1 to 5 mg kg-1. Morphine 6-glucuronide induced retching and vomiting at lower doses than morphine and at a maximal dose induced more retching and vomiting than morphine. 2. The emesis induced by both morphine and morphine 6-glucuronide was abolished by the preadministration of naloxone (0.5 mg kg-1 s.c.). 3. The 5-HT3 receptor antagonists granisetron and ondansetron (1 mg kg-1, s.c.) failed to abolish or reduce emesis induced by either compound. 4. At a high-dose (5 mg kg-1), morphine but not morphine 6-glucuronide failed to induce emesis and abolished the emesis induced by the cytotoxic drug, cyclophosphamide (200 mg kg-1, i.p.). 5. Preliminary pharmacokinetic studies of intravenous and subcutaneous morphine and morphine 6-glucuronide revealed that morphine 6-glucuronide accounts for less than 1% of the metabolic product of morphine in the ferret. Peak plasma levels of the two compounds after their subcutaneous administration were obtained within 10 min. The metabolic profile of morphine was not dose-dependent. There was no relationship between plasma level and emetic response for either compound.