Morphine metabolites

Abstract

Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The analgesic properties of M6G were recognised in the early 1970s and more recent work suggests that M6G might significantly contribute to the opioid analgesia after administration of morphine. The analgesic potency of M6G after intracerebroventricular (ICV) or intrathecal (IT) administration in rats is from 45-800 timer greater than that of morphine, depending on the animal species and the experimental antinociceptive test used. Furthermore, the development of a sensitive high-performance liquid chromatography (HPLC) assay for the quantitative determination of morphine, M6G and M3G has revealed that M6G and M3G were present in abundance after chronic oral morphine administration and that the area under the plasma concentration-time curve exceeded that of morphine. M3G has been found to antagonise morphine and M6G induced analgesia and ventilatory depression in the rat, which has led to the hypothesis that M3G may influence the development of morphine tolerance. M3G exhibits no analgesic effect after ICV or IT administration. Some studies do, however, indicate that M3G may cause non-opioid mediated hyperalgesia/allodynia and convulsions after IT administration in rats. These observations led to the hypothesis that M3G might be responsible for side-effects, hyperalgesia/allodynia and myoclonus seen after high-dose morphine treatment.

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“…Beside detoxification however, biotransformation reactions catalyzed by UGT enzymes in a minority of cases, can result in bioactivation of molecules. Reactive intermediates and toxic metabolites can be liberated with detrimental consequences [9][10][11].…”

Review and Recommendations for Drug Testing in Substance Use Treatment Contexts

“…A specific assay developed for the detection of morphine and its metabolites showed that after peroral morphine treatment, M6G and M3G were heavily concentrated and thus the area under the plasma time-curve was much greater than that of morphine itself. This finding led to the conclusion that these two metabolites may have a vital mediating role in the clinical and side-effects of morphine treatment [105].…”

“…Although morphine is almost totally absorbed from the gastro-intestinal tract, a thorough first pass metabolism of morphine leads to a low and varying bioavailability of approximately 19-47% [105]. The potency of some other opiates can be thought of in…”

“…Approximately 90% of ingested morphine is converted into metabolites. Some of these metabolites are analgesics themselves including codeine and morphine-6-glucuronide will appear [105].…”

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“…In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine [35]. Although M6G contributes to the analgesic effect of morphine, the M3G metabolite produces neurotoxicity [21,36].…”