Glucuronides, aromatic

Carvedilol is extensively metabolised with less than 2% of the dose excreted unchanged in the urine (Neugebauer et al. 1987). The primary metabolic pathways include glucuronidation, aromatic... 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

Cerniglia CE, JP Freeman, RK Mitchum (1982b) Glucuronide and sulfate conjugation in the fungal metabolism of aromatic hydrocarbons. Appl Environ Microbiol 43 1070-1075. 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

The synthesis, glucuronidation and hepatic transport of new aromatic congeners of bilirubin have also been followed by an RP-HPLC method. The chemical strucutres of bilirubin derivatives are shown in Fig. 2.160. 

J.O. Brower, D.A. Lightner and A.F. McDonagh, Aromatic congeners of bilirubin synthesis, stereochemistry, glucuronidation and hepatic transport. Tetrahedron 57 (2001) 7813-7827. 

Collier et al. (10) demonstrated that HPLC was an effective technique for the separation of aromatic hydrocarbon metabolites in exposed marine organisms. Radioactive bioconversion products were studied in liver and gall bladder of coho salmon dosed with H-naphthalene. Quantitative identifications of glucuronide, sulphate, dihydrodiol, glycoside, and 1-naphthol derivatives were obtained. Three additional polar compounds of unknown structure were found. A typical HPLC profile is shown in Figure 2. 

NNAL 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanol NNAL-gluc 4-(methylnitrosammo)-l-(3-pyridyl)-l-butanol glucuronide NNK 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone TSNA tobacco-specific nitrosamines PAH ftolycylcic aromatic hydrocarbons... 

N-Demethylation 10,11-epoxidation aromatic hydroxylation N-oxidation N-glucuronidation... 

Morphine has two nucleophilic sites that may be glucuronidated, a 3-hydroxy group on an aromatic ring and an alcoholic 6-hydroxy group. 

The drug is concentrated in estrogen target tissues, such as the ovaries, uterus, vaginal epithelium, and breasts. Hydroxylation and glucuronidation of the aromatic rings are the major pathways of metabolism excretion occurs primarily in the feces. 

Thus, sulfate conjugation and acetylation may be involved in the metabolic activation of N-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of p-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

N- Glucuronides have been isolated as urinary or biliary metabolites of many aromatic and aliphatic amines, the reaction being of minor quantitative importance in comparison to N- acetylation and other C- or A/-oxidative processes (see (B-80MI10909)). The only reported example of glucuronidation at a tertiary alicyclic nitrogen appears to be in... 

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