Phenolic glucuronide conjugate

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... 

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. 

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). 

Cytochrome P4502E1, also microsomally located, catalyzes the hydroxylation of phenol to form hydroquinone (and to a much lesser extent catechol), which is then acted upon by the phase II enzymes (Benet et al. 1995 Campbell et al. 1987 Gut et al. 1996 McFadden et al. 1996). All three enzyme systems are found in multiple tissues and there is competition among them not only for phenol but for subsequent oxidative products, like hydroquinone. As a consequence, the relative amount of the products formed can vary based on species, dose and route of administration. In vivo, the gastrointestinal tract, liver, lung, and kidney appear to be the major sites of phenol sulfate and glucuronide conjugation of simple phenols (Cassidy and Houston 1984 Powell et al. 1974 Quebbemann and Anders 1973 ... 

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3 -phosphoadenine-5 -phosphosulfate) with alcohols and phenols. The conjugates are acids, as in the case of glucuronides. In this respect, they differ from conjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol... 

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. 

Diamond GL, Anders MW, Tremaine LM, et al. 1982. Salicylate enhancement of renal glucuronide conjugation and tubular excretory transfer of phenols. Drug Metab Dispos 10 573-578. 

The metabolic fate of benzene can be altered in fasted animals. In nonfasted rats that received an intraperitoneal injection of 88 mg of benzene, the major metabolites present in urine were total conjugated phenols (14-19% of dose), glucuronides (3-4% of dose), and free phenol (2-3% of dose). However, in rats fasted for 24 hours preceding the same exposure, glucuronide conjugation increased markedly (18-21% of dose) (Cornish and Ryan 1965). Free phenol excretion (8-10% of dose) was also increased in... 

The primary metabolite of benzene is phenol. Phenol is excreted as glucuronide and sulphate conjugates in urine. Total phenolic metabolites (phenol, phenyl sulfate, and phenyl glucuronide) have been determined by hydrolyzing urine samples either enzymatically or by acid, then extracting the phenol with solvent. Phenol is then measured by GC or HPLC techniques. Enzymatic hydrolysis coupled with GC/FID has been reported the detection limit is 1 mg/L and recovery is excellent (92-98%) (Buchet 1988). Acid hydrolysis followed by HPLC provides quantitative recovery ( 100%) and a detection limit of 0.01 nmol/g (Murray and Adams 1988). Sulfate and glucuronide conjugates... 

Disposition in the Body. Slowly but completely absorbed following oral administration. It appears to undergo significant first-pass metabolism bioavailability about 70%. After intravenous administration, about 57% of a dose is excreted in the urine and 30% in the faeces over a period of 21 days less than 10% of the dose is excreted as unchanged drug. The principal metabolite is the desmethyl derivative, which has been shown to be active in animals, but hydroxylation also occurs to form phenolic derivatives which may be further converted to aromatic methoxy ethers or excreted as glucuronide conjugates A -oxidation also occurs and maprotiline A -oxide has been reported to be active numerous minor metabolites have been identified in urine. 

Particle Beam Liquid Chromatography/Mass Spectrometry of Phenols and Their Sulfate and Glucuronide Conjugates... 

PB-HPLC-MS of Phenols and Conjugates. The SAX chromatographic separation of phenols, sulfates, and glucuronides is described in detail elsewhere (12). Briefly, a 25 cm x 4.6 mm SAX column (Supelco, Bellefonte, PA) is used with an acetonitrile-pH 4.5 ammonium formate buffer (2 3) mobile phase at a flow rate of 1.5 mL/min. Under these conditions, the nine model compounds were resolved to baseline in less than 20 minutes. 

---