N-Glucuronides

N-Hydroxy arylamines readily form glucuronide conjugates, but in contrast to the N-hydroxy arylamides, these are N-glucuronides which are unreactive and stable at neutral pH. The N-glucuronides are readily transported to the lumens of the urinary bladder and intestine where they can be hydrolyzed to the free N-hydroxy arylamines by mildly acidic urine or by intestinal bacterial 3-glucuronidases (13,14). Non-enzymatic activation of N-hydroxy arylamines can occur in an acidic environment by protonation (15,16) of the N-hydroxy group (VIII) as well as by air oxidation (reviewed in 17) to a nitrosoarene (IX). 

The second pathway is direct glucuronidation which leads to generation of three isomeric N-glucuronides 8 (R( = Me, R2 or R3 or R4 = Glue). 

Interestingly, slices of human small intestine also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism of the drug. 

Chiu SH, Huskey SW. Species differences in N-glucuronidation. Drug Metab Dispos 1998 26(9) 838-847. 

Tsukamoto, H., Yoshimura, H. and Tatsumi, K. (1963) Metabolism of drugs. XXXV. Metabolic fate of meprobamate. (3). A new metabolic pathway of carbamate group - the formation of meprobamate N-glucuronide in animal body. Chemical S[ Pharmaceutical Bulletin, 11, 421. 

In a series of studies on 2-amino-A-phenylthiazole (Piscaine), a fish anesthetic, Suzuki and co-workers (24) isolated and identified an N-glucuronide metabolite (2-amino-A-phenylthiazole-2-N-g-mono-D-glucopyranosiduronic acid) from medaka (Oryzias latipes), rainbow trout, and carp (Cyprinus oarpio) (Figure l). 

Benowitz ML, Jacob P 3rd, Fong I, Gupta S (1994) Nicotine metabolic profile in man comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268 296-303 Benowitz NL, Perez-Stable EJ, Eong 1, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291 1196-1203 Benowitz NL, Griffin C, Tyndale R (2001) Deficient C-oxidation of nicotine continued. Chn Pharmacol Ther 70 567... 

Yamanaka H, Nakajima M, Katoh M, Kanoh A, Tamura O, Ishibashi H, Yokoi T (2005a) Trans-3 -hydroxycotinine O- and N-glucuronidations in human liver microsomes. Drug Metab Dispos 33 23-30... 

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

Amines may form N-glucuronides that, unlike 0-glucuronides, are resistant to bacterial p-glucuronidases. 

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... 

Ether n-Glucuronides of Compounds with Reduced Rings ... 

Other drugs almokalant, carvedilol, carbamazepine (N-glucuronidation), clonixin, cyclosporin A, epirubicin, ezetimibe, Maxipost, tacrolimus... 

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