Paracetamol sulfation

FIGURE 7.15 Continuous-flow CEC-NMR spectra (a) Paracetamol glucuronide (b) paracetamol sulfate and (c) endogenous hippurate. (Reproduced from Pusecker, K. et al. Anal. Commun. 1998, 35, 213-215. With permission from RSC publishers.)... 

Figure 13.2.6 On-flow contour plots (600 MHz) of the (a) CE-NMR, and (b) pressurized CEC-NMR separations of the paracetamol metabolites obtained from a human urine extract A, paracetamol glucoronide B, paracetamol sulfate C, hippuric acid...

The ability to identify metabolites and biotransformed products in biological fluids during separation is a considerable challenge. The potential application of CE-NMR and CEC-NMR for analysis of metabolites in biofluids has been demonstrated [51,52], For example, CE-NMR has successfully analyzed the major metabolites of paracetamol in human urine [51]. Two major metabolites, paracetamol glucuronide and paracetamol sulfate conjugates, as well as endogenous material (hippurate) have been characterized. Comparison of chemical shifts has confirmed the presence of these compounds. The estimated amount that can be detected in this study with a S/N of 3 is —10 ng. 

A 30-year-old man and a 66-year-old woman had taken paracetamol 1 g intermittently for headaches and other non-specific indications. Routine blood testing showed thrombocjdopenia (50 x 10 /1 and 45 x 10 /1 respectively). They both stopped taking paracetamol, and their platelet counts rose to normal within 7-10 days. Their sera contained antibodies (IgG or IgA) that recognized normal platelets in the presence of the metabolite paracetamol sulfate. 

Fig. 16 Effect of paracetamol granule size on tablet hardness. Curve 1 paracetamol granules with no added surfactant curve 2 paracetamol granules with 0.2% w/v sodium lauryl sulfate. (From Ref. 81.)...

The influence of sorbitol in specific formulations has also been reported [41-44]. In a paracetamol formulation consisting of sorbitol, sodium lauryl sulfate, and Aerosil, it was found that an increase in sorbitol and sodium lauryl sulfate content caused a decease in tablet hardness. This... 

The source of sulfate may be dietary or generated by oxidative metabolism of cysteine. PAPS can become depleted when large amounts of a foreign compound conjugated with sulfate, such as paracetamol, are administered. 

Other co-substrates possibly limited in supply are inorganic sulfate and glycine for conjugation these may be important factors in paracetamol hepa to toxicity and salicylate poisoning, respectively (chap. 7). 

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 sulfate facilitates elimination of the drug from the body and diverts the compound away from potentially toxic pathways (see chap. 7). Alternatively, a reactive metabolite may be converted into a stable metabolite. For example, reactive epoxides can be metabolized by epoxide hydrolase to stable dihydrodiols. 

It may relieve the saturation of sulfate conjugation, which occurs during paracetamol overdose. 

Dosages and routes of administration Codeine is used orally in single doses of 30 to 60 mg up to a total dose of 240 mg per day for pain relief. Codeine is used in the form of different salts such as hydrochloride, phosphate and sulfate. To increase the duration of action, slow-release preparations have been developed. Codeine is often combined with other analgesics e.g. acetyl salicylic acid or paracetamol. For cough inhibition lower doses are sufficient. 

Paracetamol might have a similar effect to ascorbic acid, that is competition with ethinylestradiol for sulfation capacity in the gut. Paracetamol significantly reduced the AUC of ethinylestradiol sulfate but had no effect on plasma levonorgestrel concentrations... 

In six healthy women, a single dose of paracetamol 1 g significantly increased the AUC of ethinylestradiol by 22% and reduced the AUC of ethinylestradiol sulfate (353). Plasma concentrations of levonorgestrel were unaltered. This interaction could be of clinical significance in women taking oral contraceptives who take paracetamol regularly or suddenly stop taking it, but it is doubtful whether it has any practical repercussions. 

Figure 4.1 Pseudo-2D plot of continuous-flow 1 H LC-NMR data obtained on human urine after dosing with paracetamol (1). The resonances from the glucuronide (2) and sulfate (3) conjugate metabolites of paracetamol and their ID slices are shown...

Although quercetin may stimulate UGT, it inhibits human hepatic sulfation of resveratrol, acetaminophen, dopamine, (-)-salbutamol, minoxidil, and paracetamol in vitro.69,98-101 This inhibition may be chemopreventive, as activation of some promutagens occurs via SULT reactions.68 However, SULT inhibition may also lead to the accumulation of some xenobiotics and possible toxicity. The magnitude of inhibition by quercetin of SULT appears dependent on the isoform because SULT1A3 is less affected than other isoforms, suggesting a tissue-dependent effect of quercetin.69... 

Paracetamol, its glucuronide, sulfate metabolites/model solutions DPV Working electrode GCE Reference electrode Ag/Ag/Cl Supporting electrolyte Britton-Robinson buffer (pH 3.29) Dissolving in the supporting electrolyte LOD 3.27-5.09 pM LOQ 1.09-1.70 pM [84]... 

Magnesium oxide is a basic compound and as such can react with acidic compounds in the solid state to form salts such as Mg(ibuprofen)2 or degrade alkaline-labile drugs. Adsorption of various drugs onto magnesium oxide has been reported, such as antihistamines, antibiotics (especially tetracyclines), salicylates, atropine sulfate, hyoscyamine hydrobromide, paracetamol, chloroquine, and anthranilic acid derivatives have been reported to adsorb onto the surface of magnesium... 

The principal sites for sulfation reactions are the liver and kidneys, although an important site, especially after oral administration of drugs, is the small intestine. Sulfation in the gut can seriously affect the bioavailability of some drugs such as paracetamol (see Figure 5.3) and is the main reason why adrenaline (epinephrine) is not effective when given orally... 

Paracetamol (known as acetaminophen in the USA) is N-acetyl-para-aminophenol (Figure 25.11). It has the same detoxification pathways as phenol and also carries the risk of inducing methemoglobinemia. To be on the safe side, it should not be used as an intravenous analgesic during a full-face phenol peel, so as not to saturate the detoxification pathways. Paracetamol is also an intermediate in the pathway for detoxification of aniline derivatives, before hepatic glucuronide and sulfate conjugation allow them to... 

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