Glucuronidation

Glucuronidation glucuronidation a well-known phase II detoxification reaction that acts as a pathway for eliminating many drugs, endogenous substances substances produced by the body such as hormones, glucuronidation, neurotransmittersestrogensmold toxinsand cancer-causing toxins.

Federal government websites often end in. The site is secure. Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases UGTs into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces; the formation of glucuronides by UGT enzymes and the polarized excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides.

Glucuronidation

Glucuronidation is often involved in drug metabolism of substances such as drugs , pollutants, bilirubin , androgens , estrogens , mineralocorticoids , glucocorticoids , fatty acid derivatives, retinoids , and bile acids. These linkages involve glycosidic bonds. Glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase. UDP-glucuronic acid glucuronic acid linked via a glycosidic bond to uridine diphosphate is an intermediate in the process and is formed in the liver. The substances resulting from glucuronidation are known as glucuronides or glucuronosides and are typically much more water - soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces via bile from the liver. Hormones are glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of potential therapeutics. Sometimes toxic substances are also less toxic after glucuronidation. The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism.

For example, glucuronidation, Mrp4 is found in the basolateral membrane of glucuronidation prostatic glandular cell, but has also been localized to the apical membrane of rat kidney tubule cells.

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Federal government websites often end in. The site is secure. Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases UGTs into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces; the formation of glucuronides by UGT enzymes and the polarized excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations.

Glucuronidation

Federal government websites often end in. The site is secure. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. The world today is embattled with an increasing paucity of effective therapeutic agents or regimen for many pathological conditions, as well as the menace of drug resistance and adverse effects of available drugs [ 1 ].

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It is also said to stimulate glucuronidation. J Pharm Pharmacol 55 — Gu et al. Download as PDF Printable version. In conclusion, systemic glucuronide levels are often not determined by the UGT enzyme activities alone but also by the action of efflux transporters that mediate the distribution of glucuronides into the systemic circulation. Van de Steeg et al. Mrp7 is capable of effluxing various amphipathic anions such as beta-estradiol- beta-d-glururonide Chen et al. In rat perfusion model, Mrp2 and Bcrp1 were shown to efflux naringenin glucuronide to intestine and compensate for each other Xu et al. Mol Pharmacol 57 — Peng et al. Pharmacogenetics 10 — Meng et al. Eur J Pharm Sci 27 — In efflux transporter-deficient mice, it was shown that both MRP2 and BCRP mediate the biliary excretion of droxydiclofenac acyl glucuronide Lagas et al. Transl Res —

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J Pharm Sci 96 — Efflux Transporters Involved in Glucuronide Excretion Phase II metabolites of drugs such as glucuronides, once formed, uses efflux transporters to exit the cell. Acta Anaesthesiol Scand 41 — Specific transporting mechanisms of Mrp5 and Mrp6 are unclear. In the lumen, the glucuronides can either be excreted in the feces or hydrolyzed back to the aglycone. In case of rats, both Ugt1a and Ugt2b subfamilies have been observed to be present. Local Recycling. Glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase. Drug Metab Rev 38 — Pharmacogenet Genomics 15 — From hepatocytes, both intestinal- and hepatic-generated glucuronides are then excreted into bile and systemic circulation by the apical and basolateral hepatic efflux transporters, respectively. Arch Toxicol 86 —