Glucuronidation opioids

Opioids are easily absorbed subcutaneously and intramuscularly, as well as from the gastrointestinal tract, nasal mucosa (e.g., when heroin is used as snuff), and lung (e.g., when opium is smoked). About 90% of the excretion of morphine occurs during the first 24 hours, but traces are detectable in urine for more than 48 hours. Heroin (diacetyhnorphine) is hydrolyzed to monoacetylmorphine, which is then hydrolyzed to morphine. Morphine and monoacetylmorphine are responsible for the pharmacologic effects of heroin. Heroin produces effects more rapidly than morphine because it is more lipid soluble and therefore crosses the blood-brain barrier faster. In the urine, heroin is detected as free morphine and morphine glucuronide (Gutstein and Akil 2001 Jaffe et al. 2004). 

Lotsch J, Zimmermann M, Darimont J, et al Does the Al 18G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity Anesthesiology 97 814-819, 2002... 

MOR were comparable (10 ng mL4), whereas those for DHC and EMOR were about fourfold lower. Furthermore, glucuronides were shown to react like the corresponding free opioids. Validation with real urine samples was performed with identification of the peaks by capillary electrophoresis-ion-trap mass spectrometry (CE-MS) after solid-phase extraction. 

Mignat C, Wille U, Ziegler A. (1995). Affinity profiles of morphine, codeine, dihydrocodeine, and their glucuronides at opioid receptor subtypes. Life Sci. 56(10) 793-99. 

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

Codeine phosphate is still used for diarrhea predominantly based on hypermotility but the longer-acting loperamide is more convenient and has less central nervous system effects. Codeine has an exceptionally low affinity for opioid receptors and its effects are due to the fact that it is converted for approximately 10% to morphine. The active metabolite of morphine, morphine-6-glucuronide, may also accumulate during repeated administration of codeine to patients with impaired renal function. 

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. 

The clearance of morphine and its active metabolite, morphine-6-glucuronide depends on adequate renal function. The elderly are particularly susceptible to accumulation of the drugs, hence respiratory depression and sedation. Morphine, like all opioids, passes through the placenta rapidly and has been associated with prolongation of labor in pregnant women and respiratory depression in the newborn. 

Wahlstrom, A., Lenhammar, L., Ask, B., Rane, A. Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol. Toxicol. 75(1), 23-27, 1994. 

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. 

In neonates, and especially in premature infants, the mechanism for glucuronide conjugation is poorly developed. Renal function is also very inefficient. The pharmacokinetics of morphine in neonates is thus markedly different from that in older children and adults. This, together with age-related differences in the development of opioid receptors, may explain their increased sensitivity to morphine. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

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). 

Coffman BL, King CD, Rios GR, et al. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 1998 26(l) 73-77. 

Hollt, V. A polymorphism (A118G) in the mu-opioid receptor gene affects the response to morphine-6-glucuronide in humans. Pharmacogenetics 2002,12 1-2. 

Lotsch, J. et al. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002,12 3-9. 

Microdialysis was used to assess morphine 6-beta-D-glucuronide (M6G) and morphine brain distribution in extracellular fluid after systemic administration in rats (Stain-Texier). M6G penetrated into the brain, was distributed and trapped preferentially than morphine in the extracellular fluid and therefore was available to bind at opioid receptors, explaining how M6G induces more potent central analgesia than morphine. 

---