Fate of Morphine

Morphine having once been administered to an animal has never been assembled again in its entirety as pure morphine (1). Some is eliminated unchanged in the urine and feces some is conjugated and some can be isolated from the tissues but a considerable part of the dose escapes recovery and no recognizable equivalent of breakdown products has been found to balance the deficit. 

Prior to 1940 incidental observations and comments were made suggesting that morphine may be conjugated in the body. However, the majority of the quantitative determinations prior to 1940 were based on the assumption that all of the morphine present could be liberated as free base by saturating the urine with sodium bicarbonate. They were concerned with free mor phine. The determination of free morphine does not yield a complete story on the fate of morphine, but data on free morphine need not be relegated to a forgotten limbo on the basis of the subsequent discovery of two combined forms of morphine in the urine (Thompson and Gross, 96). 

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The metabolic fate of morphine and its derivatives in mammals has been extensively investigated, and the formation of metabolites by glucuroni-dation at C-3 and C-6 (to produce 125 and 126), sulfate formation at C-3 to produce 127, N-dealkylation and oxidation, and O-methylation and... 

Another summary with special reference to the chemical structure of opium derivatives and allied synthetic substances and their pharmacodynamic action is supplement No. 138 to the Public Health Reports of the U.S. Public Health Service entitled Studies on Drug Addiction and pubUshed in 1938 (2). Synthetic analgesics have been considered subsequently in many review s. Extensively consulted in the preparation of this article were the reviews by Fellows and Ullyot (3), Lee (4), Wikler (5), Isbell and Fraser (6), Beckett (7), Schaumann (8), and Schoen (9). This review will mainly be concerned with analgesia, addiction, and fate, of morphine and related analgesics. 

Court, M.H., Krishnaswamy, S., Hao, Q., Duan, S.X., Patten, C.J., von Moltke, L.L. and Greenblatt, D.J. (2003) Evaluation of 3 -azido-3 deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes specificity and influence of the UGT2B72 polymorphism. Drug Metabolism and Disposition The Biological Fate of Chemicals, 31, 1125—1133. 

Distribution and Fate About one-third of morphine in the plasma is protein-bound after a therapeutic dose. Morphine itself does not persist in tissues, and 24 hours after the last dose, tissue concentrations are low. 

Recently very important contributions on the fate of analgesics have been made by the Department of Pharmacology and Experimental Therapeutics of the University of California in San Francisco. Among their important papers is the study, by Elliott, Tolbert, Adler, and Anderson (99), of morphine labeled with in the iV-methyl group. 

Thus the addict is excreting morphine more rapidly in the urine and is converting morphine more rapidly to carbon dioxide than does a normal subject. About 1/17 of the injected morphine is accounted for in the expired air of the addict in 24 hr. and only 1 /30 in the expired air of the normal subject. There has been a 50% increase in the ability of the addict to convert the methyl group of morphine to carbon dioxide as compared with a normal subject. The ability to excrete morphine residues has been increased about 20 %. However, the increase in the ability to excrete morphine residues in the urine accounts for 8 times as much of the increased ability of the addict to handle morphine, as does the increased ability to oxidize the methyl group of morphine. (Little can be said at present of the fate of the normorphine residue on loss of the methyl group. There also faintly remains the possibility that transmethylation between the N-methyl of morphine and some methyl donor such as choline may be involved, and that a conversion of morphine to normorphine or other nor-residue may not occur.)... 

Sproll C, Perz RC, Lachenmeier DW (2006) Optimized LC/MS/MS analysis of morphine and codeine in poppy seed and evaluation of their fate during food processing as a basis for risk anlaysis. J Agr Food Chem 54(15) 5292-5298... 

Fairbairn and El-Masry (1967), studying the fate of [ C]-labeled morphine (formula on page 192) in Pap aver somniferum, found that part of the radioactivity could be detected among sugars and amino acids. None of these radioactive metabolites were identified (see Fairbairn and Wassel, 1964 Fairbairn and El-Masry, 1968 Fairbairn et ai, 1968a,b) however. 

Fairbairn JW, El-Masry S (1967) The alkaloids of Papaver somniferum L. V. Fate of the end-product alkaloid morphine. Phytochemistry 6 499-504 Fairbairn JW, El-Masry S (1968) The alkaloids of Papaver somniferum L. VI. Bound morphine and seed development. Phytochemistry 7 181-187 Fairbairn JW, Steele MJ (1980) Bound forms of alkaloids in Papaver somniferum andP. bracte-atum. Phytochemistry 19 2317-2321... 

Eew studies have been carried out on the biliary excretion of organic compounds in man, but Elliott ef al. (1954), while investigating the fate of C-labeled morphine in man, passed a duodenal tube in one of their subjects and took samples at intervals for 24 hours. Ey assuming that all the radio-activitj in the duodenal samples came frtim the bile and that the 24-hour bile volume was 600 ml, they were able to calculate that 7% of tlie dose was excreted in the bile, which agreed well with the amount excreted in thi feces in this time. 

The toxicological or cumulative effect of illicit drugs on the ecosystems has not been studied yet. Moreover, their fate and transport in the environment is to a big extent still unknown. Due to their physical-chemical properties (octanol-water partition coefficient, solubility, etc.) some of them, such as cannabinoids, are likely to bioaccumulate in organisms or concentrate in sediments whereas the rest, much more polar compounds, will tend to stay in aqueous environmental matrices. However, continuous exposure of aquatic organisms to low aquatic concentrations of these substances, some of them still biologically active (e.g., cocaine (CO), morphine (MOR) and MDMA) may cause undesirable effects on the biota. 

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