Conjugation sulphate

Walle, U. K., Pesola, G. R., Walle, T., Stereoselective sulphate conjugation of salbutamol in humans comparison of hepatic, intestinal and platelet activity, Br. J. Clin. Pharmacol. 1993, 35, 413-418. 

Eaton EA, Walle UK, Wilson HM, Aberg G, Walle T (1996) Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells. Br J Clin Pharmacol 41 (3) 201—206. 

Watson D, Taylor GW, Murry S. 1985. Thermospray liquid chromatography negative ion mass spectrometry of steroid sulphates conjugates. Biomed Mass Spectrom 12 ... 

The metabolites of ondansetron have been examined in urine and bile from rat and dog. The major pathways for metabolism of ondansetron are A-demethylation and hydroxylation Scheme 7.7). However, whereas A-de-methylation predominates in dog, this is only a minor metabolic route in rat. Hydroxylation may occur at the 6, 7 or 8 position in the carbazolone ring. Hydroxy metabolites of ondansetron are excreted predominantly as glucuronide or sulphate conjugates. Studies with immobilised glucuronyl-transferase (Heath, S.E., personal communication) have demonstrated that O- and A-glucuronidation of ondansetron metabolites may occur. 

N2. Noir, B. A., De Walz, A. T., and Garay, A. R., Studies on the bilirubin sulphate conjugate excreted in human bile. Biochim. Biophys. Acta 222, 15-27 (1970). 

The analgesic paracetamol is largely excreted in the urine of adults as the glucuronide, only around 30% appearing as the sulphate. When human foetal liver cells were incubated with paracetamol, however, they produced the sulphate conjugate but no glucuronide. 

Figure 7.10 Metabolism of paracetamol. With therapeutic doses, paracetamol is metabolised to the glucuronide and sulphate conjugates. With higher doses these pathways become saturated and metabolism proceeds via die P-450-mediated route, with the formation of the toxic metabolite benzoquinone. This is normally metabolised by conjugation with glutathione. When glutathione is depleted benzoquinone is free to interact with cellular macromolecules, leading to cellular damage.

Mulder GJ, Kroese ED, Meerman JHN. The generation of reactive intermediates from xe nobio tics by sulphate conjugation and their role in drug toxicity. In Gorrod JW, Oelschlager H, Caldwell J, eds. Metabolism of Xenobiotics. London Taylor Francis, 1988. 

The plasma protein binding of diclofenac is greater than 99.5 % and the plasma elimination half-life is between 1 and 2 h. The metabolites of diclofenac, 4 -hydroxy-diclofenac, 5-hydroxydiclofenac, 3 -hydroxy-diclofenac, and 4 ,5-dihydroxydiclofenac are excreted as glucuronide and sulphate conjugates in the urine ( 65%) and in the bile (-35%). 

Paracetamol reaches peak plasma concentrations within the first hour after oral administration and shows only a low tendency for plasma protein binding at therapeutic concentrations. The elimination half-life is between 1 and 3 h. Paracetamol is metabolized mainly in the liver and excreted in the urine as glucuronide and sulphate conjugates. The metabolic pathway of paracetamol is shown in Schemes 66 and 67 ... 

Scheme 66 Formation of the glucuronide and sulphate conjugates of paracetamol.

Salicylamide is readily absorbed from the gastrointestinal tract and distributed to all body tissues but the drug does not bind appreciably to plasma proteins. Several studies had been reported in literatures dealing with the absorption of salicylamide and its plasma concentration (20), (21), (22), (23). It is rapidly excreted in the urine mainly as the glucuronide and sulphate conjugates. Salicylamide is metabolized in human entirely as shown in Scheme 1. 

Table 9.3 Phase II reactions. These normally produce pharmacologically inert metabolites but a few metabolites, such as N-acetylisoniazid and the sulphate conjugates of phenacetin, are toxic...

Diamond G, Quebbemann AJ. 1979. Rapid separation of p-nitrophenol and its glucuronide and sulphate conjugates by reversed phase high-performance liquid chromatography. J Chromatogr 177 368- 371. 

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... 

Orzechowski A, Schwarz L R, Schwegler U et al. 1995. Benzene metabolism in rodent hepatocytes role of sulphate conjugation. Xenobiotica 25(10) 1093-1102. 

Glutathione depletion can occur in malnourished people and alcoholics. The dominant metabolic pathway in neonates and children is sulphate conjugation. Glucuronide conjugation matures more slowly (the urinary glucuronide to sulphate ratio increases throughout childhood from 0.4 in neonates to 2 in adults) [7]. 

Glucuronide and sulphate conjugates, and the cysteine and mercapturic acid conjugates (formed from inactivation of NAPQI by glutathione), are excreted in the urine. 

Metoclopramide 80% 1-2 hours 30-40% Low hepatic extraction (<30%). Sulphate conjugation and oxidation reactions via CYP2D6 and CYP3A4 [9] <25% [9] 5-6 hours (up to 14 hours in cirrhotics [10]) ... 

Orally administered oestrogens undergo extensive first-pass metabolism in the small intestinal mucosa and liver by a hydroxysteroid dehydrogenase. These metabolites are converted to glucuronide and sulphate conjugates. Unlike ethinylestradiol, oestradiol is readily oxidised to... 

Major metabolite (sulphate conjugate) Boldenone (17) -) Nandrolone (17) -) Testosterone (17) -)... 

In those cases where a suitable antibody for radioimmunoassay is not available, a full multi-component screening procedure is necessary, and also needs to be undertaken as a confirmatory test in cases where the nature of the anabolic steroid is not known. The full analysis involves the separation of the glucuronic acid and sulphate conjugate fractions and their separate hydrolysis followed by GC-MS of their silyl or methoxime-silyl derivatives. It should be noted that the sulphatase in Helix pomatia will not hydrolyse the sulphate conjugates of the 1713-hydroxy steroids, which require mild acid hydrolysis. 

Prepare a 10 mm internal diameter column of Sephadex LH-20 (see Reagent Appendix) using a slurry of 2 g of the resin in chloroform methanol (17 3). Apply to the column the dissolved residue obtained above and elute with 30 ml of chloroform methanol (17 3) to obtain the glucuronic acid conjugates. Carry out a second elution using 50 ml of chloroform methanol (1 1) to obtain the sulphate conjugates. Evaporate the two eluates separately in a rotary film evaporator. 

Hydrolyse the sulphate conjugates by dissolving the residue in 10 ml of ethyl acetate containing 0.1 ml of sulphuric acid and incubating at 37° for 18 hours. The ethyl acetate solutions from both hydrolysates are treated as follows. Wash the ethyl acetate solution with two 5-ml portions of 2M sodium hydroxide, followed by one wash with saturated sodium chloride solution, and evaporate the solutions to dryness in a rotary film evaporator. 

Sulphate conjugates are formed with hydroxy compounds (e.g. alcohols and phenols) or aromatic amines. For example, morphine-3-(9-ethereal sulphate is a minor metabolite of morphine and N-phenylsulphamic acid is a metabolite of aniline. Sulphate conjugates are strong acids and are readily excreted in the urine they are of relatively little importance in drug metabolism. 

Disposition in the Body. Readily absorbed from the skin and mucous membranes. Metabolised to 4-aminophenol and 4-acetamidophenol which are excreted in the urine as glucuronide and sulphate conjugates. 7V-Phenylsulphamic acid (aniline N-sulphate) is also a metabolite. The main toxic effect of aniline, the formation of methaemoglobin, is thought to be due to an oxidation product of aniline, phenylhydroxylamine. 

Disposition in the Body. Rapidly and almost completely absorbed after oral administration absorption is reduced at gastric pH levels above 2 and delayed after food. It is almost entirely eliminated in the faeces via the bile, less than 5% being excreted in the urine. Carbenoxolone is excreted mainly as the glucuronide conjugate together with small amounts as the sulphate conjugate of )5-glycyrrhetic acid (enoxolone). 

Disposition in the Body. Rapidly absorbed after oral administration, peak plasma concentrations being attained within 0.25 to 1 hour. About 10% of a dose is excreted in the urine in 17 days mostly as the glucuronide and sulphate conjugates. 

Disposition in the Body. Well absorbed after oral administration. Metabolised by N- and O-demethylation followed by sulphate or glucuronic acid conjugation. The major metabolite is dextrorphan, (+)-3-hydroxy-Y-methylmorphinan ( + )-3-hy-droxymorphinan has also been identified. About 50% of a dose is excreted in the urine in 24 hours, mostly as the glucuronide and sulphate conjugates of the metabolites about 8% of a dose is excreted as unchanged drug in 6 hours. 

Disposition in the Body. Rapidly but incompletely absorbed after inhalation or oral administration. It undergoes extensive first-pass metabolism by sulphate conjugation. About 35% of an oral dose is excreted in the urine in 24 hours, mainly as the inactive sulphate conjugate, and less than 2% as unchanged drug about 40% of an oral dose is eliminated in the faeces. 

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