Metabolism morphine

Andersen G, Christrup L, Sjogren P. Relationships among morphine metabolism, pain and side effects during long-term treatment an update. J Pain Symptom Manage 2003 25(1 ) 74—91. 

A limited number of small single-dose studies have demonstrated that morphine metabolism is impaired in patients with decompensated cirrhosis, and half-life can be doubled. Information on multiple morphine doses in cirrhotic patients is lacking, but because of the demonstrated prolonged half-life in single-dose studies, accumulation could occur, and an increased dosing interval of approximately twofold is recommended in some reports. 

Correia MA, Krowech G, Caldera-Munoz P, et al. Morphine metabolism revisited. II. Isolation and chemical characterization of a glutathionylmorphine adduct from rat liver microsomal preparations. Chem Biol Interact. 1984 51(l) 13-24. 

Cone EJ, Heit HA, Caplan YH, et al. Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine. J Anal Toxicol 2006 30 1-5. 

Suski M, Bujak-Gizycka B, Made] J, Kacka K, Dobrogowski J, Woron J, Olszanecki R, Korbut R. Co-admini-stration of dextromethorphan and morphine reduction of post-operative pain and lack of influence on morphine metabolism. Basic Clin Pharmacol Toxicol 2010 107 680-4. 

Wasan AJ, Michna E, Janfaza D, Greenfield S, Teter CJ, Jamison RN (2008) Interpreting urine drug tests prevalence of morphine metabolism to hydromorphone in chronic pain patients treated with morphine. Pain Med 9 918-923... 

Morimoto S, Suemori K, Moriwaki J, Taura F, Tanaka H, Aso M, Tanaka M, Hiroshi Suemune H, Shimohigashi Y, Shoyama Y (2001) Morphine metabolism in the Opium poppy and its possible physiological function. J Biol Chem 2001 276 38179-38184... 

Miller RJ, JoUes C, Rapoport H (1973) Morphine metabolism and noimoiphine in Papaver somniferum. Phytochemistry 12 597-603... 

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

Morphine and its derivatives continue to be considered the gold standard for alleviating pain. Morphine is metabolized in the liver via N-dealkylation and glu-coronidation at the third (M3G) or sixth position (M6G). Although M3G are the most common metabolites (accounts for 50% of the metabolites produced), they elicit no biological activity when bound to MOR. It is the M6G metabolite (accounts for 10% of the metabohtes produced) that elicits the nociceptive/analgesic effect upon binding to the p opioid receptor (Dahan et al. 2008). M6G is predominately eliminated via renal excretion. 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

UDP-glucuronyltransferases catalyze the addition of glucuronic acid onto phenol, hydroxyl and carboxylic acid functions of molecules. They are expressed in many tissues of the body, including the liver and intestine [2-5], Microsomes from human intestines have been shown to metabolize UDP-glucuronyltransferase substrates including p-nitrophenol [6], 1-naphthol, morphine, and ethinylestradiol [4]. The relative rates of metabolism of these substrates in liver and intestinal microsomes are shown in Table 13.1. 

The answer is c. (Hardman, pp 543—544. Katzang, p 2533) Fentanyl is a chemical relative of meperidine that is nearly 100 times more potent than morphine. The duration of action, usually between 30 and 60 min after parenteral administration, is shorter than that of meperidine. Fentanyl citrate is only available for parenteral administration intramuscularly and intravenously. Tran sbuc cal ( lollipop ) and transdermal patches avoid first-pass metabolism of fentanyl. 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

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... 

The metabolism of heroin is of interest in connection with its pharmacological activities. Earlier opiate -receptor binding studies led to the belief that heroin is a prodrug acting through its metabolites 6-acetylmorphine and morphine [95]. However, heroin is now known to activate (5-receptors, whereas morphine activates -receptor and 6-acetylmorphine acts at both receptor types [96]. Thus, the pharmacodynamic profile of heroin results from both direct and metabolite-mediated effects. 

When heroin is administered, it is rapidly converted to 6-monoacetylmorphine and then to morphine in the brain. Heroin is also more lipid soluble, suggesting that its increased potency is due to increased distribution into the brain. The major metabolic pathway for morphine is... 

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