Drug glucuronidation

R. J., In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance, J. Pharmacol. Exp. Ther. 2002, 301, 382-390. 

Liston HL, Markowitz JS, DeVane CL (2001) Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21(5) 500-515... 

Miners, J. O., Smith, P. A., Sorich, M. J., McKinnon, R. A., and Mackenzie, P. I. (2004). Predicting human drug glucuronidation parameters Application of in vitro and in silico modeling approaches. Annu. Rev. Pharmacol. Toxicol. 44 1-25. 

Miners JO, Robson RA, Birkett DJ. Gender and oral contraceptive steroids as determinants of drug glucuronidation effects on clofibric acid elimination. Br J Clin Pharmacol 1984 18(2) 240-243. 

Soars MG, Riley RJ, Findlay KA, et al. Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney. Drug... 

Verbeeck, R.K. (1982) Glucuronidation and disposition of drug glucuronides in patients with renal failure. A review. Drug Metabolism and Disposition, 10, 87-89. 

The liver is the principal organ responsible for xenobiotic metabolism. One of its major roles is to convert lipophilic nonpolar molecules to more polar water-soluble forms. The drug molecule (a xenobiotic) can be modified by phase I reactions, which alter chemical structure by oxidation, reduction, or hydrolysis or by phase II reactions, which conjugate the drug (glucuronidation or sulfation) to create more water-soluble forms. Typically, both phase I and phase II reactions occur. Most drug metaboHsm takes place in the microsomal fraction of the hepatocytes, where many environmental chemicals and endogenous biochemicals (xeno-biotics) are also processed by the same mechanisms. 

Attaccalite, S., Carotenuto, P. and Laufer, R. (2005) Determination of drug glucuronidation and UDP-glucuronosyltransferase selectivity using a 96-well radiometric assay Drug Metabolism and Disposition The Biological Fate of Chemicals, 33, 812-819. 

Benet, L. Z. and Spahn, H. (1988) Acyl migration and covalent binding of drug glucuronides—potential toxicity mediators. Colloq. INSERM 173, 261-269. 

At present, it is not clear whether interindividual variability in rates of drug glucuronidation is more appropriately ascribed to genetic polymorphism or to host factors such as age, sex, disease, diet, or other environmental influences. However some genetic polymorphisms have been associated with hyperbilirubinemia and with some cancers. 

Efflux pumps also help to eliminate the metabolites of drugs from systemic circulation. For example, most drug glucuronide-conjugates are MRP2 and/or BCRP substrates (Adachi et al., 2005) while most sulfate conjugates are BCRP substrates (Adachi et al., 2005 Zamek-Gliszczynski et al., 2005). 

Miners JO, Smith PA, Sorich MJ, McKinnon RA, Mackenzie PL Predicting human drug glucuronidation parameters application of in vitro and in silica modeling approaches. Annu Rev Pharmacol Toxicol 2004 44 1-25. 

Glucuronides of phenolic compounds have generally been assumed to be rapidly excreted in vivo and to be pharmacologically inactive, but several studies are demonstrating that some drug glucuronides may be pharmacologically active [80, 81]. 

Analysis of Human Drug Glucuronidation and Prediction of In Vivo Metabolic Clearance. 

---