Pharmacokinetics of morphine and its metabolites in freshwater rainbow trout (Oncorhynchus mykiss)

Abstract

In this study, we injected morphine sulfate IP into rainbow trout and measured the concentration of morphine and all potential metabolites in plasma using LC-MS/MS at a series of times after the injection. The pharmacokinetics of morphine were similar to those previously reported for seawater-acclimated rainbow trout, i.e. they were about one order of magnitude slower than in similarly sized mammals. The only metabolite of morphine present in the plasma was morphine-3-beta-D-glucuronide (M3G); morphine-6-beta-D-glucuronide (M6G) was not detected. M3G gradually increased after the morphine injection, peaked about 2 days later, then gradually decreased. In mammals, M3G plasma levels exceed morphine levels extremely rapidly, i.e. in less than an hour, regardless of dose, route of administration, or species. In trout, it took 2 days for M3G levels to exceed morphine levels. This is the first study of the metabolites of morphine in any ectotherm. We conclude that trout can metabolize morphine, but at a rate much slower than in mammals.

Pharmacokinetics of morphine after intramuscular injection in common goldfish Carassius auratus and Atlantic salmon Salmo salar

“…Goldfish and salmon belong to different orders of teleosts, thus differences might be expected. The parameters also corresponded well with similar values reported by Newby et al (2008) for rainbow trout, but contrasts with the reported half-life of elimination for goldfish that was found to be 37 h after intraperitoneal (i.p.) injection (Newby et al 2009).…”

“…M3G is essentially inactive, or may even antagonise the antinociceptive effects of morphine (Smith et al 1990, Hewett et al 1993, Andersen et al 2003, whereas M6G has analgesic effects in mammals (reviewed by Dahan et al 2008). In the only study of its kind, M3G, but not M6G was detected in the plasma of rainbow trout (Newby et al 2008).…”

“…M3G is essentially inactive, or may even antagonise the antinociceptive effects of morphine (Smith et al 1990, Hewett et al 1993, Andersen et al 2003, whereas M6G has analgesic effects in mammals (reviewed by Dahan et al 2008). In the only study of its kind, M3G, but not M6G was detected in the plasma of rainbow trout (Newby et al 2008).To the authors' knowledge, the pharmacokinetics of morphine has not been previously studied in Atlantic salmon, and the distribution of morphine in different tissues has not been described in any teleost species.The aims of this study were to (1) describe the pharmacokinetics of morphine and the metabolites M3G and M6G, after intramuscular (i.m.) injection in common goldfish Carassius auratus and in the Atlantic salmon Salmo salar, and (2) illustrate the whole-body distribution of morphine following i.m.…”

“…However, the doses used have been high compared to those needed to obtain effects in mammals, with 40 to 3000 mg morphine kg -1 being injected intraperitoneally or intramuscularly in fish, compared to 1 mg kg -1 for rats (King et al 2007). The few existing studies on the pharmacokinetics of opioids in fish have revealed interspecific differences in the disposition of morphine (Newby et al 2006, Newby et al 2008, Newby et al 2009). Therefore, more research is needed on the pharmacokinetics of morphine and its metabolites in different fish species before analgesic protocols can be suggested and validated.…”

Simultaneous analysis of gemfibrozil, morphine, and its two active metabolites in different mouse brain structures using solid‐phase extraction with ultra‐high performance liquid chromatography and tandem mass spectrometry with a deuterated internal standard

“…There are several methods used to detect morphine or its main metabolites M3G and M6G in animal tissues, but not in brain samples [19][20][21][22][23][24]. However, most of them used different molecules as internal standard (IS) such as donepezil, codeine, and naloxone hydrochloride [19][20][21][22].…”