V-glucuronidation

Disposition in the Body. Readily absorbed after oral administration. About 90% of a dose is excreted in the urine in 24 hours, with about 10 to 20% of the dose as unchanged drug and the remainder as metabolites, mainly 2-hydroxypropylmeprobamate and meprobamate V-glucuronide. About 10% of the dose is eliminated in the faeces. 

V. Glucuronide-derived Covalent Binding of Diflunisal to Bladder Tissue of Rats and Its Modulation by Urinary pH and Beta-glucuronidase," Biochem. Pharmacol. 46(7), 1175-1182 (1993). 

F. F. Kadlubar, J. A. Miller, and E. C. Miller, Hepatic microsomal V-glucuronidation and nucleic acid binding of V-hydroxy arylamines in relation to urinary bladder carcinogenesis, Cancer Res. 37, 805-814 (1977). 

A typical CYP reaction length is 1-2 h, but CYP activity can survive longer at 37 °C. Figure 9.3 shows that product turnover of the CYP reactions occurred over a 6 h incubation (Li, unpublished results). UGT activity can last longer than 24 h [23], With accumulation of product, secondary reactions, such as further oxidation of product or hydrolysis of glucuronide, may become noticeable. Therefore, monitoring the reaction with HPLC-U V-MS is critical for identifying the best time to terminate the reaction. 

Zenser, T.V., Lakshmi, V.M. and Davis, B.B. (1999) Human and Escherichia coli /3-glucuronidase hydrolysis of glucuronide conjugates of benzidine and 4-aminobiphenyl, and their hydroxy metabolites. Drug Metabolism and Disposition The Biological Fate of Chemicals, 27, 1064—1067. 

Aniline is rapidly and extensively metabolized following oral administration. In the pig and sheep, approximately 30% of a 50-mg/kg dose of 14C-labeled aniline was excreted in the urine, as measured by 14C activity, within 3 h after administration, whereas approximately 50% of the dose was excreted in rats. Within 24 h, more than half the administered dose was excreted by pigs and sheep and 96% of the dose was excreted by rats. Fecal radioactivity was low. A-acetylated metabolites accounted for most of the excretion—/V-acetyl-/>-aminophenyl glucuronide being the primary metabolite in sheep and pig urine and /V-acetyl-/>-aminophenyl sulfate being the primary metabolite in the rat (Kao et al. 1978). Biologic monitoring of workers exposed to aniline showed that /i-aminophenol constituted 15-55% of the parent compound in the urine the o- and ra-isomers were also formed (Piotrowski 1984). 

Intravenous or intramuscular injection urine collected over 24-h period after single application of radiolabeled famphur Intramuscular injection Urinary radioactivity was due to the unchanged O-desmethyl compound (13-24%) A/,/V-dimethyl sulfamoylphenyl glucuronide (32-33%) O./V-bisdesmethylfamphur (31-34%) and /V-methyl sulfamoylphenyl glucuronide (8—15%) 8... 

Figure 4. Time course of accumulation of phenol red and glucuronide in the bile and urine. The lines are model predictions and the symbols are experimental data ( )> bile (B) (A), urine (V) (9).

Like imines, some oximes are known to undergo metabolic hydrolysis by a nonenzymatic mechanism. Cyclohexanone oxime (11.69), an intermediate in the synthesis of polycaprolactam or Nylon-6, is a good example with which to begin our discussion. Following administration to male rats by various routes, cyclohexanone oxime undergoes rapid metabolism, and only trace amounts of the parent compound can be recovered in the urine [104], Although cyclohexanone (11.70) represented a small fraction of the urinary metabolites, most of the dose was recovered as glucuronides of cyclohexa-nol (11.71) and of cis- and /ran.v-cyclohexanc-1,2-diol. 

T. V. Zenser, V. M. Lakshmi, B. B. Davis, Human and Escherichia coli /3-Glucuronidase Hydrolysis of Glucuronide Conjugates of Benzidine and 4-Aminobiphenyl, and Their Hydroxy Metabolites , Drug Metab. Dispos. 1999, 27, 1064 - 1077. 

Shipkova, M., Armstrong, V.M., Wieland, E., Niedmann, P.D., Schiitz, E., Brenner-WeiC, G., Voihsel, M., Braun, E. and Oellerich, M., Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Brit. J. Pharmacol., 1999,126, 1075. 

Approximately 16 % of the dose is hydroxylated, 5.8 % at the 5 position (SOH) and 10.2 % at 6 position (SCH2OH). No glucuronide metabolites were formed. Acetylation accounted for 12.7 % of the dose, while the recovery of the parent drug was 13.9 %. Thus approximately 58 % of the administered dose is lost after i.v. application (Table III). The renal clearance of the hydroxy and acetylated metabolites were 10 to 50 fold higher than that of SDM. 

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