Morphine 3- and 6-glucuronides

The analgesic morphine and three metabolites (morphine-3- and 6-glucuronide, hydromorphone) were isolated from plasma and separated on a 35°C C g column (multi-channel electrochemical detector set at 0.2 y 0.35 V, and 0.4 V and X = 275 nm, ex 345 nm, em for morphine-3-glucosonide only). A 25/75 acetoni-trile/water (50 mM phosphate pH 2.1 with 2.5 mM sodium dodecyl sulfate) mobile phase generated baseline resolution in 24 min. Linear ranges of 5-600 ng/mL and detection limits of 0.2 ng/mL were reported [1334]. 

Isolation and Identification of Morphine 3- and 6-Glucuronides, Morphine 3,6-Diglucuronide, Morphine 3-Etherel Sulfate, Normorphine and Normorphine 6-Glucuronide as Morphine Metabolites in Humans J. Pharm. Sci. 66(9) 1288-1293 (1977) CA 88 4463z... 

FIGURE 7.3 Structures of bilirubin diglucuronide and the 3- and 6-glucuronides of morphine. 

Bogusz MJ, Maier RD, Erkens M, Driessen S. 1997. Determination of morphine and its 3- and 6-glucuronides, codeine, codeine-glucuronide and 6-monoacetylmorphine in body fluids by liquid chromatography atmospheric pressure chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 703 115. 

Heroin is rapidly hydrolyzed in vivo to 6-monoacetylmorphine (257) and thence to morphine (1) (see also p. 26). N-Demethylation and O-demethyla-tion are significant metabolic routes in animals, with the former oxidative process leading to normorphine (258) from 1, and norcodeine (259) from 2, which may in turn be eliminated as their 3- and 6-glucuronides, respectively. 

Reverse phase methods were also used to assay dimethylaminoetoposide (2) together with a stereoisomer and their AT-demethylated metabolites in the urine of cancer patients. A related paper discusses an analytical method for etoposide and isomers in plasma. Other work describes the isolation of glucuronides of metronidazole (3) and its hydroxy metabolite (4) by preparative HPLC methods, and the antipyrene metabolite derivatives 5-7 were identified by thermospray LC-MS methods. In the area of the metabolites of narcotics, two papers have described the reverse phase-HPLC analysis of morphine and its 3-and 6-glucuronides in biological samples. In the first case, fluorescence detection was used, in the latter electrospray MS procedures. Codeine and seven glycosidic metabolites have also been analysed by reverse phase-HPLC procedures with UV or electrochemical detection. ... 

Hupka et al. [29] developed a method for the determination of morphine and its phase II metabolites, morphine-3-beta-D-glucuronide and morphine-6-beta-D-glucuronide in the blood of heroin victims. The method is based on immunoaffinity SPE, RP-HPLC isocratic separation (mobile phase 90% lOmmol KH2PO4, 2mmol 1-heptanesulfonic acid, adjusted to pH 2.5 with H3PO4 and 10% acetonitrile flow rate 1.5 mL/min), and laser-induced native fluorescence detection. 

Morphine and morphine 3-p-D-glucuronide were separated on two different 4.6-mm-diameter X 50-mm-long columns with 3-p.m particles.29 Column A was Cl8-silica run at 1.4 mL/min and column B was bare silica run at 2.0 mL/min. 

Murphy, C.M., and Huestis, M.A. (2005) LC-ESI-MS/MS analysis for the quantification of morphine, codeine, morphine-3-beta-D-glucuronide, morphine-6-beta-D-glucuronide, and codeine-6-beta-D-glucuronide in human urine. Journal of Mass Spectrometry, 40,1412-1416. 

Carrupt, P.-A. Testa, B. Bechalany, A. El Tayar, N. Descas, P. Perrissoud, D., Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpectedly high lipophilicity, J. Med. Chem. 34, 1272-1275 (1991). 

Per-O-acylated glycosyl iodides are stable at room temperature and can be purified on a silica gel column and stored at 0 °C. Stachulski and coworkers [202] synthesized methyl 2,3,4-tri-O-pivaloyl-glucopyranuroate iodide, which is a stable solid at 20 °C and can be stored for months at room temperature or for more than a year at 0 °C. The X-ray crystal structure of this compound, the first one of this class, shows a typical chair structure. Importantly, such a disarmed and stable iodide can be coupled with primary and secondary steroidal alcohols using I2 as a promoter, as demonstrated by the synthesis of morphine-6-glucuronide, an analgesic [202], The glycosyl donor ability... 

Rotshteyn Y, Weingarten B. 1996. A highly sensitive assay for the simultaneous determination of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in human plasma by high-performance liquid chromatography with electrochemical and fluorescence detection. Ther Drug Monit 18(2) 179-188. 

Kilpatrick GJ, Smith TW. (2005) Morphine-6-glucuronide Actions and mechanisms. Med Res Rev 25 521-544. For further information PAION. Press release 3 November 2008. Available at http //www.paion.com/. 

The majority of their metabolites are inactive with a few notable exceptions, such as morphine-6-glucuronide, which produces an analgesic effect normeperidine and norpropoxyphene, which produce excitatory but not analgesic effects and 6-(3-naltexol, which is less active than naltrexone as an antagonist but prolongs the action of naltrexone. Excretion of the metabolites requires adequate renal function, since excretion by routes other than the urine are of minor importance. 

Lotsch, J., A. Stockmann, G. Kobal, K. Brune, et al., Pharmacokinetics of morphine and its glucu-ronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers, Clin. Pharmacol. Ther., 60(3), 316-325, 1996. 

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