Glucuronides formation

FIGURE 2.14 Phase 2 biotransformation—conjugation. (1) Glucuronide formation. (2) Sulfate formation. (3) Glutathione conjugation. 

Portmann and co-workers then studied the kinetic pathways in man for hydroxynalidixic acid, the active primary metabolite.(26) The rate constants for glucuronide formation, oxidation to the dicarboxylic acid and excretion of hydroxynalidixic acid were calculated. Essentially total absorption of hydroxynalidixic acid was found in every case. Good agreement between experimental and theoretical plasma levels, based on the first order rate approximations used for the model, was found. Again, the disappearance rate constant, kdoi was found to be very similar for each subject, although the individual excretion and metabolic rate constants varied widely. The disappearance rate constant, k was defined as the sum of the excretion rate constant, kg j and the metabolic rate constants to the glucuronide and dicarboxylic acid, kM-j and kgj, respectively. 

Lech, J. J., Statham, C. N. Role of glucuronide formation in the selective toxicity of 3-trifluoromethyl-4-nitrophenol (TFM) for the sea lamprey comparative aspects of TFM uptake and conjugation in sea lamprey and rainbow trout. Toxicol. Appl. Pharmacol. (1975), 37(1) 150-158. 

Allylic methyl group hydroxylation and oxidation to carboxylic acid glucuronide formation... 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

A8. Arias, I. M., and London, I. M., Bilirubin glucuronide formation in vitro demonstration of a defect in Gilbert s disease. Science 126, 563-564 (1957). 

AlO. Arias, I. M., Gartner, L. M., Seifter, S., and Furman, M., Prolonged neonatal unconjugated hyperbilirubinemia associated with breast feeding and a steroid, pregnane-3a,20/3-diol, in maternal milk that inhibits glucuronide formation in vitro. J. Clin. Invest. 43, 2037-2047 (1964). 

Fll. Flodgaard, H. J., and Brodersen, R., Bilirubin glucuronide formation in developing guinea pig liver. Scand. J. Clin. Lab. Invest. 19, 149-155 (1967). 

Hepatic 0-dealkylation and glucuronide formation appear to be major pathways of biotransformation. Only about 10% of orally administered prazosin is excreted in the urine. Plasma levels of prazosin are increased in patients with renal failure the nature of this interaction is unknown. 

Absorption from the intestinal tract is usually good. Food delays but does not reduce absorption. The drug is distributed in body fluids and has a half-Ufe of about 8 hours. High levels are found in plasma and cerebrospinal fluid (CSF). Less than 20% binds to plasma proteins. Metronidazole is metabolized by oxidation and glucuronide formation in the liver and is primarily... 

Since the early years of this century a large number of biosynthetic D-glucuronides have been isolated and numerous investigations into the origin of D-glucuronic acid and the mechanism of D-glucuronide formation have been made. It is mainly with these topics that this article will be concerned. 

Evidence of D-glucuronide formation has been obtained for compounds too numerous to mention. In a large number of cases crude non-crystalline glucuronide-containing material has been isolated and in many instances the glucuronides themselves or derivatives of them have been obtained crystalline. 

Thus it seems certain that glucuronide formation is closely related to carbohydrate metabolism, but the details of the mechanism are, as yet, unknown. The important points which have to be elucidated refer to the immediate precursor or precursors of D-glucuronic acid and to the nature of the conjugation process, for example, whether D-glucuronic acid is built up on the aglycon molecule or whether direct union of the acid with the aglycon can occur. 

Figure 14.5 Intestinal resveratrol metabolic pathway proposed after oral administration using Caco-2 monolayers. SULT and UGT enzymes shown in bold represent the predominant contribution to sulfate and glucuronide formation.

Ionizing Radiation. In general, ionizing radiation reduces the rate of metabolism of xenobiotics both in vivo and in enzyme preparations subsequently isolated. This has occurred in hydroxylation of steroids, in the development of desulfuration activity toward azinphosmethyl in young rats, and in glucuronide formation in mice. Pseudocholinesterase activity is reduced by ionizing radiation in the ileum of both rats and mice. 

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