Paracetamol elimination

Ray K, Sahana CC, Chaudhuri SB, et al. 1993. Effects of trichloroethylene anaesthesia on salivary paracetamol elimination. Indian J Physiol Pharmacol 37(1) 79-81. 

Caffeine citrate 120 mg increased the AUC of a single 500-mg dose of paracetamol in 10 healthy subjects by 29%, increased the maximum plasma levels by 15% and decreased the total body clearance by 32%. The decrease in time to maximum level and increase in absorption rate did not reach statistical significance. However, in another study, although caffeine slightly increased the rate of absorption of paracetamol, it had no effect on the extent of absorption. Moreover, a third study states that caffeine decreased plasma paracetamol levels and AUC and increased paracetamol elimination in healthy men. Caffeine is commonly included in paracetamol preparations as an analgesic adjuvant. Its potential benefit and the mechanisms behind its possible effects remain unclear. 

After oral administration, paracetamol is completely absorbed from the gastrointestinal tract with peak plasma concentrations being reached in less than an hour. The drug is eliminated by conjugation with glucoronic acid in the liver. The chemical structure is liable to oxidation. 

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. 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see 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. 

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 ... 

GRAPEFRUIT JUICE PARACETAMOL t half-life of paracetamol. White grapefruit juice t plasma concentrations in 1 hour, while pink grapefruit juice caused the t in 2 hours Attributed to t elimination half-life of paracetamol caused by grapefruit juice Be aware... 

Although investigation should always precede analysis, there is no need to wait for full completion of tile questionnaire because some poisons are so common that they should always be eliminated. These include ethanol, aspirin, paracetamol, barbiturates, and carbon monoxide. Many of tiiese can be checked by rapid analytical probing tests before a full group screen is applied. Completion of the following analytical probing tests will, in many cases, provide clues to the nature of the poison. 

Disposition in the Body. Readily absorbed after oral administration. It is hydrolysed in the blood to aspirin and paracetamol, and about 85% of a dose is excreted in the urine in 72 hours by the normal metabolic routes for these substances. About 15% of a dose is eliminated in the faeces. 

Chemicals that are easily absorbed into the body are usually soluble in fat, which makes them difficult to eliminate from the body (for example, paracetamol). For them to be eliminated in the urine (which is basically water), the molecule has to be water-soluble, and chemicals are rarely soluble in both fat and water. Consequently the body has a mechanism for... 

A particular animal species may have a deficiency and be unable to metabolize and so eliminate a chemical. For example, the domestic cat has a particular deficiency which affects the handling of the drug paracetamol. If pet owners give doses of paracetamol to their cats, it may kill them. Understanding such differences is crucial for the use of veterinary drugs. 

Early side effects often include fever and flu-like symptoms, which are generally alleviated or eliminated by paracetamol they are mostly temporary and of no clinical significance. Late side effects depend on the individual case and dosage they are influenced by coexistent diseases (e. g. diabetes) or psychic disposition. (201) There have been reports of numerous and different side effects. When they occur, a dose reduction is necessary in 3—25% of cases (depending on the dose) IFN treatment has to be discontinued in 3-5%. (s. tab. 34.9)... 

It may be prepared by the esterification of acetyl salicylic acid and paracetamol with the elimination of a mole of water. 

In a study in 6 healthy subjects, lansoprazole 30 mg once daily for 3 days increased the peak level of paracetamol (given as a single 1-g dose in solution) by 43%, and decreased the time to peak paracetamol levels by half (from about 35 to 17.5 minutes). However, lansoprazole had no effect on the AUC and elimination half-life of paracetamol. ... 

Three studies report alterations in the pharmacokinetics of chloramphenicol hy paracetamol. The first was conducted in 6 adults in intensive care after an ohservafion thaf fhe half-life of chloramphenicol was prolonged hy paracefamol in children wifh kwashiorkor. The addition of 100 mg of intravenous paracetamol inereased the half-life of chloramphenicol in the adults from 3.25 to 15 hours. Ttowever, this study has been criticised because of potential errors in the method used to calculate the half-life, the unusual doses and routes of administration used, and because the pharmacokinetics of the chloramphenicol with and without paracetamol were calculated at different times after the administration of chloramphenicol. ft has also been pointed out that malnutrition (e.g. kwashiorkor) can increase the elimination rate and AUC of chloramphenicol independently of paraeetamol. ... 

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