Chemistrys - Excretion & Paracetamol Essay

Investigateurinary elimination of paracetamol in adult male.

Paracetamol, known as acetaminophenin the USA, is one of the most normally used analgetic and antipyretic drugsavailable nonprescription. Its common name derives from the full chemicalname: para-acetyl-amino-phenol, with thechemical expression C8Hydrogen9NO2and amolecular weight of 151.17.

Paracetamol does non hold anysignificant anti-inflammatory action and hence can non be accuratelydescribed as a non-steroidal anti-inflammatory drug ( NSAID ) , as was oncethought. Its mechanism of action is still ill understood but some studieshave suggested that it inhibits a discrepancy of the cyclo-oxygenase enzyme COX-1, which has been designated COX-3 ( Swierkosz et al. 2002 ) . Paracetamol actsmainly in the cardinal nervous system and endothelial cells, instead than inplatelets and immune cells. Boutaud and co-workers ( 2002 ) hypothesised thatthis may be explained by the high degrees of peroxides found in the latter cell types, which inhibit the action of paracetamol. There has been some argument on thesubject, with other research workers suggesting an repressive action against COX-2 ( Graham & A ; Scott 2005 ) . Further research is required to to the full clarify themechanism of action at the molecular degree.

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Metamorphosis and elimination

Following unwritten disposal andabsorption from the GI piece of land, paracetamol enters the blood and isdistributed throughout the organic structure. It is metabolised by enzymes in thehepatocytes of the liver and the bulk is converted to inactive metabolitesby junction with sulfate or glucuronide. This is so filtered out of theblood by the kidneys and into the piss, via active nephritic cannular secernment. Asmall part of paracetamol remains unchanged and passes into the urine viaglomerular filtration and inactive soaking up ( Morris & A ; Levy 1984 ) . Thereis besides a little proportion of the paracetamol that is metabolised by thecytochrome P450 system, which consequences in the formation of cysteine or glutathioneconjugates and mercapturic acid conjugates ( figure 2 ) . These merchandises ofoxidative metamorphosis are besides excreted renally ( Andrews et al. 1976 ) .

Paracetamol has a low therapeuticindex, so the curative dosage is really near to the toxic dosage. Toxicity canoccur following a individual big dosage ( & gt ; 10g ) or with chronic lower doses ( 4-5g/d ) and is normally seen as hepatotoxicity, which can ensue in deathwithin several yearss ( Wikipedia ) .

Toxicity occurs when the enzymesresponsible for catalyzing sulfate and glucuronide junction becomesaturated, coercing metamorphosis to be progressively dependent upon the cytochromeP450 system. This consequences in formation of a toxic metabolite, N-acetyl-p-benzo-quinone imine ( NAPQI ) , which is usually mopped up by bindingto the sulphydryl group of glutathione to organize inactive conjugates andmercapturic acid. Toxicity occurs when the glutathione supply becomes exhaustedand NAPQI binds randomly to molecules within the cell, such asmembranes, to do cell harm and decease, seen as acute hepatic mortification.

1 ) Major tract for normal metamorphosis

2 ) Minor tract via cytochrome P450 system produces toxic metabolite ( NAPQI ) , shown in ruddy. Normally this is detoxified by adhering to glutathione.

3 ) Toxicity occurs when tracts 1 and 2 are overloadedand NAPQI binds to molecules of the cell, doing harm.

Modifiedfrom Rang et Al. 1995.

Aim of experiment

The purpose of this experiment is toinvestigate the nephritic elimination of paracetamol, by mensurating the degrees ofparacetamol metabolites in human piss over 6 hours following an unwritten dosage of500mg. The entire elimination will be assessed utilizing the spectrophotometricmethod. From this data the riddance rate invariable ( KTocopherol) and thehalf-life ( T1/2) will be calculated. Qualitative analysis of thevarious metabolites will be conducted utilizing appropriate chemical identificationtechniques.


A standard stock solution ofparacetamol was prepared at 1mg/cm3and dilutions were made to givea scope of known concentrations. 1 centimeter3of the paracetamol solutionwas added to 1 centimeter3clean piss and 4 centimeter34M HCl, andmixed exhaustively. A clean extra was besides prepared, utilizing H2O alternatively ofurine. After an hr in a boiling H2O bath the tubings were cooled and wateradded, up to 10 centimeter3. 1 centimeter3of this hydrolysed urinesolution was added to 10 centimeter3of coloring material organizing solution, assorted and allowed to stand for40 proceedingss. The optical density of each solution was measured, utilizing thespectrophotometer, zeroing the instrument utilizing the drug free urine sample inbetween solutions. This produced the readings for the standardization curve. Thecollected timed urine samples were so processed in the same manner, adding 1 centimeter3H2O alternatively of paracetamol solution.


Known concentrations of paracetamolunderwent spectrophotometry to mensurate the optical density at 620nm. These resultswere used to bring forth a standardization curve ( figure 3 ) . The timed piss sampleswere so analysed following the same protocol and the optical density at 620nm wasused, in concurrence with the standardization curve to determine the concentrationof paracetamol in the piss. Unfortunately, half of the samples producedabsorbances outside the scope of the standardization curve. Because this curve isnon-linear, extrapolation and dilution can non be used to accurately infer theconcentration of paracetamol in the piss. For the intents of this study theconcentration for these samples has been declared as ‘greater than 800ug/cm3 ‘.This is non really satisfactory and farther experiments must be done to extendthe scope of the standardization curve to the maximal absorbancy of the timedsamples. The values of KTocopheroland T1/2have been calculatedto demonstrate the process, but are inaccurate and will necessitate revising onceaccurate concentrations have been established form the standardization curve.

Table 1:

Timed urine sample

Average optical density 620nm

Conc. ug/cm3

Vol. Urine ( milliliter )

Entire drug ( ug of paracetamol )

Elimination rate mg/h







1 hr






2 hours


& gt ; 800




3 hours


& gt ; 800




4 hours


& gt ; 800




5 hours






6 hours






Table 1 contains the absorbanceresults of the timed urine samples and the deduced concentration of paracetamolin the piss, every bit good as the hourly elimination rate. The entire sum ofparacetamol excreted over the 6 hr period was 225.3mg, which is 45 % of theorally administered dosage. Due to jobs discussed supra, this is anunderestimate of the true per centum of dosage excreted renally, which has beenfound to be 55-70 % by other surveies ( Steventon et al. 1996 ) .

When log of the elimination rate ( tantamount to entire drug excreted per hr ) is plotted against clip, a linearplot should be achieved, from which KTocopherolcan be estimated.

The incline of this consecutive lineequates to: KTocopherol/2.303, which gives a value for KTocopherolof0.094. Using the expression: Thymine1/2=0.692/ KTocopherol, the valueof T1/2= 7.36 hours.

This states that it takes the body7.36 hours to egest half of the drug administered. This is longer than the1-4 hours normally quoted for paracetamol ( Rang et al. 1995 ) , and is notsurprising given the underestimate of the paracetamol piss concentration.With proper standardization, this would be expected to diminish to nearer thepreviously found consequences.

There were no consequences for thequalitative surveies for metabolite composing, but it would be expected thatsulphate and glucuronide conjugates would represent the bulk of the sample, with a smaller measure of unchanged paracetamol, cysteine/glutathione andmercapturic acid metabolites.

These consequences merely represent oneindividual on one twenty-four hours and reproductions of this experiment are crucial.Nutritional position, recent intoxicant ingestion, cultural background, concurrentdrug use and unwellness must all be taken into history as factors that mayaffect paracetamol metamorphosis and elimination ( Riordan & A ; Williams 2002, Patel & A ; Tang 1992 ) .

Further analysis of paracetamolexcretion

. Hepatotoxicity and drug interactions

Table 2 shows how coincident usage of phenobarbital, ananti-epileptic drug, can increase the badness of liver harm caused byparacetamol disposal and its subsequent metamorphosis.

Table 2: Consequence of Phenobarbital onparacetamol induced hepatotoxicity

TreatmentDose of Paracetamol ( mg/kg ) Badness of liver mortification

None 375 1-2+

Phenobarbital 375 2-4+_________

This occurs due to metabolism ofphenobarbital by enzymes of the P450 cytochrome system, which consequences inupregulation of their production. As explained in the debut ( see fig.2 ) , P450 enzymes besides metabolise paracetamol, to organize the toxic metaboliteNAPQI. This is usually a minor tract but as the sum of P450 enzymesavailable additions, the activity of this tract besides increases. This resultsin a larger than normal sum of NAPQI, which is mopped up and inactivated byglutathione. Glutathione supplies will finally run out, which occurs soonerif the individual is malnourished. When this happens the toxic metabolite binds tocell constituents, doing mortification. To forestall this happening, such as in casesof overdose, N-acetylcysteine can be given ( Routledge et al. 1998 ) , which isrequired for glutathione synthesis and helps to hike it. This allows agreater sum of the toxic metabolite to be mopped up and reduces cell harm.

. Paracetamol metamorphosis following hepatotoxicity

Table 3:


concentrations ( ug/cm3 )

Patients Plasma

paracetamol 4 hour after 12hrsafter

Half life ( H ) consumption consumption


noliver harm ( 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 survey, theability of patients with liver harm to extinguish paracetamol from the bloodis much decreased, compared to healthy people. This is seen by the prolongedhalf-life and the high degrees of paracetamol in the plasma. The plasma leveldoes come down by 12 hour, which indicates that there is adequate functional liverreserve to metabolize some of the drug, but the degree is still really high. Toascertain whether it is merely junction that is affected, or whether all thepathways are affected every bit it would be necessary to quantify the degrees ofdifferent metabolites in the blood and piss. As junction is responsiblefor the bulk of metamorphosis, harm to all systems will still demo up asaffecting junction the most.

In theory reduced clearance of asubstance is utile for supervising the badness of liver harm, but in thecase of paracetamol it would be unwise as it could potentiate the hepatotoxiceffects and decline the liver status. It is besides unneeded as there arealready a figure of dependable blood trials for liver map and harm.


Andrews, R. S. , Bond, C. C. , Burnett, J. , Saunders, A. & A ; Watson, K. 1976 Isolation and designation of paracetamol metabolites.J Int Med Res4,34-9.

Boutaud, O. , Aronoff, D. M. , Richardson, J. H. , Marnett, L. J. & A ; Oates, J. A. 2002 Determinants of the cellular specificity of Datril as an inhibitor of prostaglandin H ( 2 ) synthases.Proc Natl Acad Sci U S A99,7130-5.

Graham, G. G. & A ; Scott, K. F. 2005 Mechanism of action of paracetamol.Am J Ther12, 46-55.

Morris, M. E. & A ; Levy, G. 1984 Renal clearance and serum protein binding of Datril and its major conjugates in worlds.J Pharm Sci73, 1038-41.

Patel, M. , Tang, B. K. & A ; Kalow, W. 1992 Variability of acetaminophen metamorphosis in Caucasians and Orientals.Pharmacogeneticss2, 38-45.

Rang, H. P. , Dale, M.M. , Ritter, J.M. 1995Pharmacology: Duke of marlborough Livingstone.

Riordan, S. M. & A ; Williams, R. 2002 Alcohol exposure and paracetamol-induced hepatotoxicity.Addict Biol7, 191-206.

Routledge, P. , Vale, J. A. , Bateman, D. N. , Johnston, G. D. , Jones, A. , Judd, A. , Thomas, S. , Volans, G. , Prescott, L. F. & A ; Proudfoot, A. 1998 Paracetamol ( Datril ) toxic condition. No demand to alter current guidelines to accident sections.Bmj317, 1609-10.

Steventon, G. B. , Mitchell, S. C. & A ; Waring, R. H. 1996 Human metamorphosis of paracetamol ( Datril ) at different dosage degrees.Drug Metabol Drug Interact13, 111-7.

Swierkosz, T. A. , Jordan, L. , McBride, M. , McGough, K. , Devlin, J. & A ; Botting, R. M. 2002 Actions of paracetamol on Coxs in tissue and cell homogenates of mouse and coney.Med Sci Monit8, BR496-503.

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