Morphine glucuronidation

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). 

Gaillard, P. Carrupt, P.-A. Testa, B., The conformation-dependent lipophilicity of morphine glucuronides as calculated from the molecular lipophilicity potential, Bioorg. Med. Chem. Lett. 4, 737-742 (1994). 

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... 

Ary K, Rona K. 2001. LC determination of morphine and morphine glucuronides in human plasma by coulometric and UV detection. J Pharm Biomed Anal 26(2) 179-187. 

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. 

Despite slower penetration into the brain (blood-brain equilibration half-life 3-16 h for MSG versus 2-4.5 h for morphine), it may be that 50% or more of the respiratory depression observed by 1 h following systemic administration of morphine is due to this metabolite. Patients with renal insufficiency have impaired elimination of morphine glucuronides and MSG makes a significant contribution to morphine intoxication in these patients. 

Stuart-Harris, R., S.P. Joel, P. McDonald, D. Currow, et al., The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine, Br. J. Clin. Pharmacol., 49(3), 207-214, 2000. 

Ishii, Y., Takami, A., Tsuruda, K., Kurogi, A., Yamada, H., and Oguri, K. (1997). Induction of two UDP-glucuronosyltransferase isoforms sensitive to phenobarbital that are involved in morphine glucuronidation. Production of isoform-selective antipeptide antibodies toward UGTl.lr and UGT2B1. Drug Metab. Dispos. 25 163-167. 

J. Huwyler, S. Rufer, E. Kusters and J. Drewe, Rapid and highly automated determination of morphine and morphine glucuronides in plasma by on-hne sohd-phase extraction and column hquid chromatography , J. Chromatogr. B 674 57-63 (1995). 

Coffman BL, Rios GR, King CD, Tephly TR (1997) Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25 1-4... 

Taylor K, Elliott S (2009) A validated hybrid quadrupole linear ion-trap LC-MS method for the analysis of morphine and morphine glucuronides applied to opiate deaths. Forensic Sci Int 187(l-3) 34 fl. doi S0379-0738(09)00085-l [pii] 10.1016/j.forsciint.2009.02.011... 

Holthe M, Klepstad P, Zahlsen K, et al. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1 28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002 58(5) 353-356. 

Calculations reported by Gaillard et al. [145] show that the lipophilicity of morphine glucuronides is conformation-dependent. These compounds exist as folded and extended conformers that differ in their partition behavior. They are hydrophilic in water and less polar in lipid environments such as membranes. 

Opioids in hair are readily detected with a variety of commercial opioid immunoassays including RIA, FPIA, and Emit. Most opioid immunoassays are formulated to detect morphine and morphine glucuronide, but also exhibit significant cross... 

Other definitive metabolites which are used in our laboratory as indicators of drug use are cocaethylene, norcocaine, A9-carboxy-tetrahydrocaimabinol (carboxy-THC) (a substance which is not found in smoke from a marijuana cigarette), and the heroin metabolites 6-MAM and morphine glucuronide. Drugs and metabolites are measured by ultrasensitive GC/MS/MS or chemical ionization ion-trap GC/MS techniques requiring 5 mg or less of sample. ... 

Gaillard, R, Carrupt, P.-A. and Testa, B. (1994a). The Conformation-Dependent Lipophilicity of Morphine Glucuronides as Calculated from their Molecular Lipophilicity Potential. Bioorg. Med.Chem.Lett., 4,737-742. 

Drugs of abuse in humait hair 1 Drugs of abuse in hurnan hair li Morphine glucuronide Amino acids/hydrpchlpric acid Toxic metals... 

For the determination of morphine in opium, Ikekawa et al.40 developed a rapid method whereby morphine and morphine glucuronide were isolated from the urine sample (50 ml) by adsorption on a charcoal column (1 g in a column of 1 cm I.D.), washed with water to remove impurities, and eluted with glacial acetic acid (20 ml). After evaporation to dryness in vacuo, the morphine glucuronide was hydrolyzed with hydrochloric acid, and the pH adjusted to 2.5 with sodium hydroxide and extracted with chloroform isopropanol (9 1). The water layer was... 

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