Glucuronide conjugates

Many authors reported poor elimination of antiepileptic drug carbamazepine [6,13,17,49, 54]. Pharmacokinetic data indicate that only 1-2% of carbamazepine is excreted unmetabolized. However, glucuronide conjugates of carbamazepine can presumably be cleaved in the sewage, and thus increase its environmental concentrations [51]. This is confirmed by its high ubiquity in the enviromnent at concentration levels of several hundred nanograms per liter in different surface waters. Due to its recalcitrant nature, it can be used as anthropogeiuc marker for the contamination of aquatic environment. 

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

There are several pharmacokinetic differences between loop diuretics. Fifty to sixty percent of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.17 In contrast, liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively.17 Thus, patients with ARF may have a prolonged half-life of furosemide. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The intravenous (IV) oral ratio for bumetanide and torsemide is 1 1, bioavailability of oral furosemide is approximately 50%, with a reported range of 10% to 100%.18... 

Hepatic metabolism No Yes oxidation and hydroxylation induces liver enzymes to increase its metabolism and other drugs Yes oxidation and conjugation Yes oxidation and glucuronide conjugation Yes glucuronic acid conjugation Induces its own metabolism in normal volunteers... 

To prepare glucuronide conjugates of products formed from initial oxidation (to yield a hydroxyl or carboxylic acid group), the oxidative metabolite should be prepared first and used as a substrate in the incubation. Alternatively, an incubation with parent drug, NADPH and UDPGA may produce the desired glucuronide. 

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. 

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). 

Fingerlings given single ip injection of 60 pg 2,3,7,8-TCDD/kg BW One week after injection, the bile contained at least 3 TODD metabolites plus the parent compound at least one of the metabolites was a glucuronide conjugate 31... 

After a single dose, elimination occurred by way of several routes catabolism to tetrachlorohydroquinone excretion of unchanged PCP and its glucuronide conjugate in urine excretion of PCP or its metabolites into bile. More than 90% was eliminated during the rapid phase, the Tb 1/2 being 13-17 h (Braun etal. 1977)... 

The major metabolic pathways of the TCAs are demethylation, hydroxyla-tion, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by microsomal oxidation followed by glucuronide conjugation. 

The short plasma half-life of dobutamine (1-2 minutes) was found by Murphy et al. (4) to be due to the rapid redistribution of the drug from the plasma to the tissue. However, plasma half-life of radioactivity following the administration of 14C-dobutamine was 1.9 hours. The major circulating metabolite is the glucuronide conjugate of 3-0-methyldobutamine. During a continuous intravenous infusion of dobutamine, the plasma level of the parent drug reach a maximum within 8 to 10 minutes, while those of the metabolites peak be-... 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Formation of. glucuronide conjugates is a major metabolic conversion for many lipid-soluble compounds. The product glucuronides are more water soluble and usually more readily excreted. The glucuronic acid donor in this reaction is... 

Substrates for the sulfotransferases include such varied compounds as primary and secondary alcohols, hydroxysteroids, phenols, organic hydroxylamines, and amines. As is the case with formation of glutathione and glucuronide conjugates, the formation of a sulfate ester usually renders a substance more polar and more readily excreted. Several reviews on the multiple forms of sulfotransferases and their specificities and properties are available (133-135). 

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