Paracetamol sulphate

Jensen, L.S., Valentine, J., Milne, R.W., Evans, A.M. The quantification of paracetamol, paracetamol glucuronide and paracetamol sulphate in plasma and urine using a single high-performance liquid chromatography assay. J. Pharm. Biomed. Anal. 24, 585-593 (2004)... 

Amphetamines (speed sulph, sulphate, uppers, wake-ups, billy whizz, whizz, whites, base) are synthetic stimulants which as medicines have been formed into a variety of tablets. Their current medical use is very limited and in fact only dexamphetamine sulphate, Dexedrine, is now available for use solely in the treatment of narcolepsy. The only other amphetamine available for medical use is methylphenidate (Ritalin) for the treatment of attention deficit syndrome in children. As a street drug, amphetamine usually comes as a white, grey, yellowish or pinky powder. The purity rate of street powders is less than 10%, the rest being made up of milder stimulants such as caffeine, other drugs such as paracetamol or substances like glucose, dried baby milk, flour or talcum powder. 

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. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Paracetamol is given orally and is well absorbed, peak plasma concentration is reached in 30 to 60 minutes. About l/3rd is bound to plasma proteins and the drug is inactivated in the liver, being conjugated to give the glucu-ronide or sulphate which are excreted in urine. 

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.

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.

Ullrich D, Sieg A, Blume R, et al. Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert s syndrome. Eur J Clin Invest 1987 17(3) 237-240. 

The metabolism of paracetamol (Figure 6.6) is an example of potential toxication. Paracetamol is metabolised primarily in the liver, via phase II metabolism, where its major metabolites include inactive sulphate and glucuronide conjugates, which are excreted by the kidneys. 

Disposition in the Body. Rapidly and completely absorbed after oral administration, with maximum plasma concentrations achieved after one to two hours. It is distributed throughout the body. The main metabolic reaction is oxidation to paracetamol through which the analgesic and antipyretic effects of the drug are chiefly exerted paracetamol is then conjugated with glucuronic acid or sulphate. A minor reaction is deacetylation of... 

Disposition in the Body. Readily absorbed after oral administration, but subject to extensive first-pass metabolism. It is metabolised mainly in the liver by O-dealkylation to paracetamol and acetaldehyde, followed by conjugation of the paracetamol with sulphate or glucuronic acid (see under Paracetamol) other reactions are deacetylation to phenetidine (/7-ethoxyaniline), N-,2-, and a-hydroxylation forming mainly 2-hydroxyphenet-idine and also 2-hydroxyphenacetin, sulphate conjugation of de-acetylated metabolites, and glutathione conjugation to form... 

However, while using microemulsion as an eluent, it should be remembered that several factors such as concentration of surfactants, co-surfactants and organic phase, pH of the aqueous phase, column temperature can influence the resolution and retention of the compounds. The microemulsions described so far are based on sodium dodecyl sulphate, short-chain alcohols such as butanol and octanol and aqueous phase of different pH values [78, 159-161]. The utility of w/o microemulsions in the normal phase HPLC analysis has also been described [162]. The microemulsion liquid chromatography (MELC) has been used for resolution of several API such as paracetamol, loratidine, simvastatin, niacinamide, fosinoprilat from their impurities or degradants or metabolic products [159-162]. 

Other co-substrates possibly limited in supply are inorganic sulphate and glycine for conjugation these may be important factors in paracetamol hepatotoxicity and salicylate poisoning, respectively (Chapter... 

Biological systems possess a number of mechanisms for protection against toxic foreign compounds, some of which have already been mentioned. Thus, metabolic transformation to more polar metabolites which are readily excreted is one method of detoxication. For example, conjugation of paracetamol with glucuronic acid and sulphate facilitates elimination of the drug from the body and diverts the compound away from potentially toxic... 

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