Urinary Excretion and Paracetamol

Investigateurinary excretion of paracetamol in man.

Paracetamol, known as acetaminophen in the USA, is one of the most commonly used analgesic and antipyretic drugs available over-the-counter. Its common name derives from the full chemical name: para-acetyl-amino-phenol, with the chemical formula C₈H₉NO₂ and amolecular weight of 151.17.

Paracetamol does not have anysignificant anti-inflammatory action and therefore cannot be accuratelydescribed as a non-steroidal anti-inflammatory drug (NSAID), as was oncethought. Its mechanism of action is still poorly understood but some studieshave suggested that it inhibits a variant of the cyclo-oxygenase enzyme COX-1, which has been designated COX-3 (Swierkosz et al. 2002). Paracetamol actsmainly in the central nervous system and endothelial cells, rather than inplatelets and immune cells. Boutaud and colleagues (2002) hypothesised thatthis may be explained by the high levels of peroxides found in the latter cell types, which inhibit the action of paracetamol. There has been some debate on thesubject, with other researchers proposing an inhibitory action against COX-2(Graham & Scott 2005). Further research is required to fully elucidate the mechanism of action at the molecular level.

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Metabolism and excretion

Following oral administration and absorption from the gastrointestinal tract, paracetamol enters the blood and is distributed throughout the body. It is metabolised by enzymes in the hepatocytes of the liver and the majority is converted to inactive metabolites by conjugation with sulphate or glucuronide. This is then filtered out of theblood by the kidneys and into the urine, via active renal tubular secretion. Asmall portion of paracetamol remains unaltered and passes into the urine viaglomerular filtration and passive absorption (Morris & Levy 1984). Thereis also a small proportion of the paracetamol that is metabolised by the thecytochrome P450 system, which results in the formation of cysteine or glutathioneconjugates and mercapturic acid conjugates (figure 2). These products ofoxidative metabolism are also excreted renally (Andrews et al. 1976).

Paracetamol has a low therapeuticindex, so the therapeutic dose is very close to the toxic dose. Toxicity canoccur following a single large dose (>10g) or with chronic lower doses(4-5g/d) and is usually seen as hepatotoxicity, which can result in deathwithin several days (Wikipedia).

Toxicity occurs when the enzymesresponsible for catalysing sulphate and glucuronide conjugation becomesaturated, forcing metabolism to be increasingly dependent upon the cytochromeP450 system. This results in formation of a toxic metabolite,N-acetyl-p-benzo-quinone imine (NAPQI), which is normally mopped up by bindingto the sulphydryl group of glutathione to form inactive conjugates andmercapturic acid. Toxicity occurs when the glutathione supply becomes exhaustedand NAPQI binds indiscriminately to molecules within the cell, such asmembranes, to cause cell damage and death, seen as acute hepatic necrosis.

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1)Major pathway for normal metabolism

2)Minor pathway via cytochrome P450 system produces toxic metabolite (NAPQI),shown in red. Normally this is detoxified by binding to glutathione.

3) Toxicity occurs when pathways 1 and 2 are overloadedand NAPQI binds to molecules of the cell, causing damage.

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Modifiedfrom Rang et al. 1995.

Aim of experiment

The aim of this experiment is toinvestigate the renal excretion of paracetamol, by measuring the levels ofparacetamol metabolites in human urine over 6 hours following an oral dose of500mg. The total excretion will be assessed using the spectrophotometricmethod. From this data the elimination rate constant (K_E) and thehalf-life (T_1/2) will be calculated. Qualitative analysis of thevarious metabolites will be conducted using appropriate chemical identificationtechniques.

METHOD

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A standard stock solution ofparacetamol was prepared at 1mg/cm³ and dilutions were made to givea range of known concentrations. 1 cm³ of the paracetamol solutionwas added to 1 cm³ blank urine and 4 cm³ 4M HCl, andmixed thoroughly. A blank duplicate was also prepared, using water instead ofurine. After an hour in a boiling water bath the tubes were cooled and wateradded, up to 10 cm³. 1 cm³ of this hydrolysed urinesolution was added to 10 cm³ of colour forming solution, mixed and allowed to stand for40 minutes. The absorbance of each solution was measured, using thespectrophotometer, zeroing the instrument using the drug free urine sample inbetween solutions. This produced the readings for the calibration curve. Thecollected timed urine samples were then processed in the same way, adding 1 cm³water instead of paracetamol solution.

RESULTS AND DISCUSSION

Known concentrations of paracetamolunderwent spectrophotometry to measure the absorbance at 620nm. These resultswere used to produce a calibration curve (figure 3). The timed urine sampleswere then analysed following the same protocol and the absorbance at 620nm wasused, in conjunction with the calibration curve to ascertain the concentrationof paracetamol in the urine. Unfortunately, half of the samples producedabsorbances outside the range of the calibration curve. Because this curve isnon-linear, extrapolation and dilution cannot be used to accurately deduce theconcentration of paracetamol in the urine. For the purposes of this report theconcentration for these samples has been declared as ‘greater than 800ug/cm^3′.This is not very satisfactory and further experiments must be done to extendthe range of the calibration curve to the maximum absorbancy of the timedsamples. The values of K_E and T_1/2 have been calculatedto demonstrate the procedure, but are inaccurate and will need revising onceaccurate concentrations have been established form the calibration curve.

Table 1:

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Timed urine sample	Mean absorbance 620nm	Conc. ug/cm3	Vol. Urine (ml) Why Are You Top for Research Papers? Our writers are Ph.D.-level pros who live for nailing the details—think deep research and razor-sharp arguments. We pair that with top plagiarism tools, free revisions to tweak anything you need, and fast turnarounds that don’t skimp on quality. Your research paper won’t just shine—it’ll set the bar.	Total drug (ug of paracetamol)	Excretion rate mg/h
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Table 1 contains the absorbanceresults of the timed urine samples and the deduced concentration of paracetamolin the urine, as well as the hourly excretion rate. The total amount ofparacetamol excreted over the 6 hour period was 225.3mg, which is 45% of theorally administered dose. Due to problems discussed above, this is anunderestimate of the true percentage of dose excreted renally, which has beenfound to be 55-70% by other studies (Steventon et al. 1996).

When log of the excretion rate(equivalent to total drug excreted per hour) is plotted against time, a linearplot should be achieved, from which K_E can be estimated.

The slope of this straight lineequates to : K_E /2.303, which gives a value for K_E of0.094. Using the formula: T_1/2 =0.692/ K_E , the valueof T_1/2 = 7.36 hours.

This states that it takes the body7.36 hours to excrete half of the drug administered. This is longer than the1-4 hours usually quoted for paracetamol (Rang et al. 1995), and is notsurprising given the underestimation of the paracetamol urine concentration.With proper calibration, this would be expected to decrease to nearer thepreviously found results.

There were no results for thequalitative studies for metabolite composition, but it would be expected thatsulphate and glucuronide conjugates would constitute the majority of the sample,with a smaller quantity of unchanged paracetamol, cysteine/glutathione andmercapturic acid metabolites.

These results only represent oneindividual on one day and replications of this experiment are crucial.Nutritional status, recent alcohol consumption, ethnic background, concurrentdrug usage and illness must all be taken into account as factors that mayaffect paracetamol metabolism and excretion (Riordan & Williams 2002, Patel& Tang 1992).

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Further analysis of paracetamolexcretion

.       Hepatotoxicity and drug interactions

Table 2 shows how concurrent use of phenobarbital, ananti-epileptic drug, can increase the severity of liver damage caused byparacetamol administration and its subsequent metabolism.

Table 2: Effect of Phenobarbital onparacetamol induced hepatotoxicity

TreatmentDose of Paracetamol (mg/kg) Severity of liver necrosis

None 375 1-2+

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Phenobarbital 375 2-4+_________

This occurs due to metabolism ofphenobarbital by enzymes of the P450 cytochrome system, which results inupregulation of their production. As explained in the introduction (see fig.2), P450 enzymes also metabolise paracetamol, to form the toxic metaboliteNAPQI. This is normally a minor pathway but as the amount of P450 enzymesavailable increases, the activity of this pathway also increases. This resultsin a larger than normal amount of NAPQI, which is mopped up and inactivated byglutathione. Glutathione supplies will eventually run out, which occurs soonerif the person is malnourished. When this happens the toxic metabolite binds tocell components, causing necrosis. To prevent this occurring, such as in casesof overdose, N-acetylcysteine can be given (Routledge et al. 1998), which isrequired for glutathione synthesis and helps to boost it. This allows agreater amount of the toxic metabolite to be mopped up and reduces cell damage.

.       Paracetamol metabolism following hepatotoxicity

Table 3:

Plasmaparacetamol

concentrations(ug/cm3)

Patients Plasma

paracetamol 4 hrs after 12hrsafter

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Half life (h) ingestion ingestion

_______________________________________________________________

noliver damage (18) 2.9 +/= 0.3 163 +/=20 29.5 +/=6

liverdamage (23) 7.2+/= 0.7 296 +/= 26 124 +/=22___

Table 3 shows that, in a study, theability of patients with liver damage to eliminate paracetamol from the bloodis much decreased, compared to healthy people. This is seen by the prolongedhalf-life and the high levels of paracetamol in the plasma. The plasma leveldoes come down by 12 hrs, which indicates that there is enough functional liverreserve to metabolise some of the drug, but the level is still very high. Toascertain whether it is just conjugation that is affected, or whether all thepathways are affected equally it would be necessary to quantify the levels ofdifferent metabolites in the blood and urine. As conjugation is responsiblefor the majority of metabolism, damage to all systems will still show up asaffecting conjugation the most.

In theory reduced clearance of asubstance is useful for monitoring the severity of liver damage, but in thecase of paracetamol it would be unwise as it could potentiate the hepatotoxiceffects and worsen the liver condition. It is also unnecessary as there arealready a number of reliable blood tests for liver function and damage.

REFERENCES

Andrews, R. S., Bond, C. C., Burnett, J., Saunders, A. & Watson, K. 1976 Isolation and identification of paracetamol metabolites. J Int Med Res 4,34-9.

Boutaud, O., Aronoff, D. M., Richardson, J. H., Marnett, L. J. & Oates, J. A. 2002 Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. Proc Natl Acad Sci U S A 99,7130-5.

Graham, G. G. & Scott, K. F. 2005 Mechanism of action of paracetamol. Am J Ther 12, 46-55.

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Morris, M. E. & Levy, G. 1984 Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans. J Pharm Sci 73, 1038-41.

Patel, M., Tang, B. K. & Kalow, W. 1992 Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics 2, 38-45.

Rang, H. P., Dale, M.M., Ritter, J.M. 1995 Pharmacology: Churchill Livingstone.

Riordan, S. M. & Williams, R. 2002 Alcohol exposure and paracetamol-induced hepatotoxicity. Addict Biol 7, 191-206.

Routledge, P., Vale, J. A., Bateman, D. N., Johnston, G. D., Jones, A., Judd, A., Thomas, S., Volans, G., Prescott, L. F. & Proudfoot, A. 1998 Paracetamol (acetaminophen) poisoning. No need to change current guidelines to accident departments. Bmj 317, 1609-10.

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Steventon, G. B., Mitchell, S. C. & Waring, R. H. 1996 Human metabolism of paracetamol (acetaminophen) at different dose levels. Drug Metabol Drug Interact 13, 111-7.

Swierkosz, T. A., Jordan, L., McBride, M., McGough, K., Devlin, J. & Botting, R. M. 2002 Actions of paracetamol on cyclooxygenases in tissue and cell homogenates of mouse and rabbit. Med Sci Monit 8, BR496-503.

http://en.wikipedia.org/wiki/Paracetamol.

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