N-glucuronide conjugation

One proposed mechanism of MBOCA excretion suggests that very little MBOCA is excreted into the bladder as the free amine since most of the MBOCA in the renal perfusate may be present in the form of the p-N-glucuronide conjugate (Cocker et al. 1990). Urine contains p-glucuronidase, and therefore, p-N-glucuronide may undergo some hydrolysis in the bladder. This is proposed as the source of free MBOCA in the urine. 

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). 

There is no information regarding the metabolism of 3,3 -dichlorobenzidine in children. However, N-acetylation (as discussed above) in humans is likely done by one of two families of N-acetyltransferases. One of these families, NAT2, is developmentally regulated (Leeder and Kearns 1997). Some enzyme activity can be detected in the fetus by the end of the first trimester. Almost all infants exhibit the slow acetylator phenotype between birth and 2 months of age. The adult phenotype distribution is reached by the age of 4-6 months, whereas adult activity is found by approximately 1-3 years of age. Also, UDP-glucuronosyltransferase, responsible for the formation of glucuronide conjugates, seems to achieve adult activity by 6-18 months of age (Leeder and Kearns 1997). These data suggest that metabolism of 3,3 -dichlorobenzidine by infants will differ from that in adults in extent, rate, or both. 

Following a 400-mg dose of C-indinavir, 83 1% (mean S.D.) (n=4) and 19 3% (n=6) of the total radioactivity was recovered in feces and urine, respectively. The radioactivity due to parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP344) is the major enzyme responsible for formation of the oxidative metabolites [28]. 

Figure 4.53 Formation of an N-hydroxy glucuronide conjugation of W-hydroxy-2-napthylamine and formation of a reactive nitrenium ion.

Manini, P. Andreoli, R. Mutti, A. Bergamaschi, E. Niessen, W. M. 1998. Determination of n-hexane metabolites by liquid chromatography/mass spectrometry. 2. Glucuronide-conjugated metabolites in untreated urine samples by electrospray ionization. Rapid Commun. Mass Spectrom., 12,1615-1624. 

Metabolites identified in urine are 3-(3,5-dichlorophenyl)-5-methyloxazolidin-2,4-dione, N-(3,5-dichlorophenyl)-2-hydroxypropionamide, O-l -carboxyethyl-N-3,5-dichloro-phenyl carbamate, and iV-(3,5-dichloro-2(or 4)-hydroxyphenyl)-2-hydroxypropionamide and its sulfate and glucuronide conjugates Plants. Undergoes hydrolysis and decarboxylation processes, giving the same metabolites as those identified in animals. 

Disposition in the Body. Absorbed after oral administration. Less than 0.5% of a dose is excreted in the urine as unchanged drug in 24 hours a metabolite, tentatively identified as an N-hydroxybenzyl-3-chloropropionamide, has been detected in the urine as a glucuronide conjugate. 

The metabolism of 6-methylelliptinium (420) in rats (bile and urine) gives rise to the O-sulfate and O-glucuronide conjugates, but no demethylation of the N-6 methyl group (260) (Scheme 68). Likewise, the HRP/H2O2 system gives rise to the ort/io-quinone 421 and the oxazolopyridocarbazole 422, when alanine is present, but not to N-6 demethylation (261). The metabolism of olivacine (4) in rats and microsomes is faster than that of ellipticine, and leads to hydroxylation at the C-7 and C-9 positions (as conjugates) (55). 

Chouini-Lalanne N, Malet-Martino MC, Gilard V, Ader JC, Martino R. Structural determination of a glucuronide conjugate of flucytosine in humans. Drug Metab Dispos I995 23(8) 8I3-7. 

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