Morphine-6-glucuronide metabolism

Metabolism Glucuronidation N-demethylation Ester hydrolysis to morphine Glucuronidation demethylation (CYP2D6) Ester hydrolysis N-demethylation N-Dealkylation, then hydroxylation N-Demethylation Plasma and tissue esterases... 

Metabolism of drugs. LX. Synthesis of codeine and morphine glucuronides... 

SKF 525-A inhibits the in vitro metabolism of several barbiturates, meperidine, aminopyrine, and codeine, the formation of morphine glucuronide, and the hydrolysis of procaine and ethylglycinexylidide. However, SKF 525-A has no significant effect on the microsomal N-demethylation of monomethyl-4-aminoantipyrine, N-methylaniline or 3-methyl-4-monomethylaminoazobenzene, the O-dealkylation of phenacetin, the hydroxylation of acetanilide, or the sulphoxidation of chlorpro-mazine. 

Fig. 7.26 Structure of morphine, which is metabolized to a more active opioid analgesic by glucuronidation at the 6 position.

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

The most important other opium alkaloid is codeine. In contrast to morphine, codeine has a high oral-parenteral potency ratio due to less first-pass metabolism. Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Approximately 10% is demethylated to morphine. The analgesic effect of codeine is due to the formation of these metabolites as codeine itself has a very low affinity for opioid receptors. The half-life of codeine in plasma is 2 hours. 

It is inactive orally because of high first pass metabolism in liver. Metabolised by glucuronidation in liver. The main use of naloxone is in the treatment of acute opioid overdose (acute morphine poisoning). It also precipitates withdrawal syndrome when administered to morphine addicts. The constricted pupils of addicts dilate after administration of naloxone. This has been used as a diagnostic tool for opioid addiction. 

Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate dosage can often be reduced in such patients. 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Ethylmorphine (Aasmundstad et al., 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O- and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides. 

Morphine is known to be metabolized by glucuronidation to two biologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (Boemer et al., 1975). M6G has high affinity for the /(-opioid receptor (Loser et al., 1996 Pasternak et al., 1987 Paul et al., 1989) and appears to be a more potent opioid agonist than morphine (Frances et al., 1992 Osborne el al., 2000 Pasternak et al., 1987 Paul el al., 1989). In contrast, M3G does not bind to ji-, 6-, or K-opioid receptors (Loser et al., 1996 Pasternak et al., 1987) and appears to be devoid of analgesic activity (Pasternak et al., 1987 Yaksh and Harty, 1988). 

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