Glucuronidation phenols

The duration of action of acetaminophen is limited by the formation of water-soluble derivatives of the phenol (glucuronide and sulfate) that are then excreted via the kidney. Protection i)f the phenol as an ether inhibits such inactivation without diminishing biologic activity. Acetylation of p-ethoxyaniline iffords the widely used peripheral analgesic, phenacetin (25). ... 

Many drugs and metabolites are metabolized by conjugation with sulfate or glucuronic acid as described in Chapter 7. Sulfate conjugates can be hydrolyzed back to the alcohol or phenol. Glucuronide conjugates can involve a wider variety of functional groups and... 

When administered orally to rats at various doses, U-91592 was completely absorbed and extensively metabolized [118]. Two metabolites (a phenol glucuronide and a glutathione adduct) were formed following initial cytochrome P450 mediated epoxidation of the heterocycle. The third metabolite was the triester (9.52, Fig. 9.11), which was also a major product of in vitro metabolism in rat liver microsomes. Interestingly, the formation of the tries-... 

Absorption - Atier ora administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10 mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax)- The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability the coefficient of variation, based on intersubject variability, was 35% to 60% for area under the curve (AUC) values. 

A postchromatographic -glucuronidase procedure has been also used for the analysis of phenolic glucuronides, such as those produced from trimethoprim (274). The enzymatic analysis of these glucuronides provided the production of the corresponding phenolic compounds, which were measured by both UV and electrochemical detection. 

Staimer, N., Gee, S.J., and Hammock, B.D., Development of a class-selective enzyme immunoassay for urinary phenolic glucuronides, Anal. Chim. Acta, 441, 27-36, 2001. 

Probenecid Diflunisal Formation CL of phenol glucuronide and acyl glucuronide decreased 45% and 54%, respectively 114... 

Schrenk D, Bock KW. 1990. Metabolism of benzene in rat hepatocytes. Influence of inducers on phenol glucuronidation. Drug Metab Dispos 18(5) 720-725. 

MMF is rapidly hydrolyzed by widely distributed esterases in blood and tissues to produce MPA. The rate hm-iting step in the clearance of MPA is its conversion to the phenolic glucuronide metabolite MPAG (Figure 33-14) via... 

The primary sites and effects of drug-drug interactions involving other medications and MPA are likely to be decreased absorption in the gastrointestinal tract, inhibition of enterohepatic cycling, and inhibition of transport of the primary phenolic glucuronide metabolite. Meal consumption just before oral intake of MMF delays absorption, causing a reduction in the maximal concentration by about... 

The biotransformation of salicylates takes place in many tissues, but particularly in the liver. The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. 

In an attempt to develop effective UGT inhibitors, transition-state based inhibitors were synthesized taking advantage of the high affinity of UGT for the UDP moiety and the structural requirement for the acceptor substrate, w.w.o)-Triphenylalkyl-UDP derivatives (Fig. 31.40) have been shown to be powerful inhibitors of UGT bilirubin isoform. In the same manner, DMSU was an efficient inhibitor of phenol glucuronidation catalysed by UGT1A6. ... 

Fig. 31.40 Active site and transition-state analogues (1) 7,7,7-triphenylheptanoic acid (2) w,(i),-triphenylalkyl-UDP (3) 3-5 -0-[[(2-decanoyl-3-phenylpropyloxycarbonyl)methyl]sulfonyl]uridine (DMSU). In insert, structure of a putative transition state analogue for the phenol glucuronidation reaction catalysed by UGT.

Mino Y, Naito T, Otsuka A, Ushiyama T, Ozono S, Kagawa Y, Kawakami J. Cyclosporine concentration-dependent increase in concentration ratio of mycophenolic acid acyl and phenol glucuronides to mycophenolic acid in stable kidney transplant recipients. Clin Biochem 2009 42(7-8) 595-601. 

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