Paracetamol pharmacokinetics

Most studies investigating paracetamol pharmacokinetics in patients with liver disease used single doses only. A 50% reduction in clearance and a corresponding increase in half-life have been seen in severe acute hepatitis, the longest half-life being seen in patients with a raised prothrombin time (PT). It may therefore be prudent to extend the dose interval in these patients. Cirrhotic patients with a low albumin and a raised PT were also noted to have a prolonged paracetamol half-life, although no accumulation or hepatotoxicity was observed when normal therapeutic doses were administered to these patients for up to five days. In contrast, cirrhotic patients with normal albumin and PT demonstrated... 

Other studies have also demonstrated similar increases in half-life when comparing paracetamol pharmacokinetics in patients with decompensated chronic liver disease to normal subjects. Patients with cirrhosis who have a normal plasma albumin concentration and PT have been shown to have a similar paracetamol half-life and clearance to those of healthy subjects. However, cirrhotic patients with a low plasma albumin and an increased PT were found to have a prolonged paracetamol half-life. Despite this, no accumulation and no evidence of hepatotoxicity was demonstrated when therapeutic doses of paracetamol were given to patients with decompensated liver diseases for three to five days [21]. 

In 11 healthy subjects, paracetamol 1 g every 6 hours for 5 doses had no effect on the pharmacokinetics of a 19-hour infusion of argatroban 1.5 micrograms/kg per minute, started with the second dose of paracetamol. In addition, argatroban had no effect on paracetamol pharmacokinetics. Paracetamol did not alter the effect of argatroban on aPTT. ... 

B. K. (1967) Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. British Journal of Pharmacology and Chemotherapy, 29, 150. 

Grattan T, Hickman R, Darby-Dowman A, Hayward M, Boyce M, Warrington S. A five way crossover human volunteer study to compare the pharmacokinetics of paracetamol following oral administration of two commercially available paracetamol tablets and three development tablets containing paracetamol in combination with sodium bicarbonate or calcium carbonate. Eur J Pharm Biopharm 2000 49 225-229. 

Prescott LF, Wright N. The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage. A pharmacokinetic study. Br J Pharmacol 1973 49(4) 602-613. 

Depre, M., van Hecken, A., Verbesselt, R., Tjandra-Maga, T. B., Gerin, M., de Schepper, P. J. Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use, Fundam. Clin. Pharmacol. 1992, 6, 259-262. 

F. Kamali, The effect of probenecid on paracetamol metabolism and pharmacokinetics. Eur. J. Clin. Pharmacol. 45 551-553, 1993. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

The half-life of paracetamol has been shown to be prolonged during acute viral hepatitis and in patients with severe chronic liver disease. Most studies were single-dose studies. One study looked at the pharmacokinetics of paracetamol (1 g) in ten patients with acute viral hepatitis (ALT increased at least tenfold and acute onset of symptoms) and 20 controls. In the hepatitis patients the paracetamol dose was given in both the acute phase and in the convalescence phase (approximately one month after complete biochemical recovery). At the time of the acute attack, peak concentrations of paracetamol did not differ significantly compared to the recovery phase, nor to the 20 controls. However, during acute hepatitis the half-life of paracetamol was significantly increased compared to the convalescent phase (3.2 h vs... 

Forrest JAH, Clements JA, Prescott LF (1982) Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7 93—107. 

Paracetamol altered the pharmacokinetics of chloramphenicol in some studies but not in others. 

The thrombin inhibitor argatroban had no effect on the pharmacokinetics of five oral doses of paracetamol 1 g 6-hourly in 12 healthy volunteers the argatroban was given as an intravenous infusion of 1.5 pg/kg/minute from hours 12 to 30 (121). 

Radovanovic J, Duric Z, Jovanovic M, Ibric S, Petrovic M. An attempt to establish an in vitro-in vivo correlation case of paracetamol immediate-release tablets. Eur J Drug Metab Pharmacokinet 1998 23(l) 33-40. 

Anderson, B., Woollard, G.A., and Holford, N.H.G. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants, and children. British Journal of Clinical Pharmacology 2000 50 125-134. 

Monshouwer, M. Witkamp, R.F. Pijpers, A. Verheijden, J.H.M. Van Miert, A.S.J.PA.M. Dose-dependent pharmacokinetic interaction between antip3nine and paracetamol in vivo and in vitro when administered as cocktail in pig. Xenobiotica, 1994, 24, 347—355... 

Ismail, S. Kokwaro, G.O. Back, D.J. Edwards, G. Effect of malaria infection on the pharmacokinetics of paracetamol in rat. Xenobiotica, 1994, 24, 527-533 [pharmacokinetics rat plasma urine extracted metabolites 3-acetamidophenol is IS]... 

Thomas, B.R. Fang, X.G. Shen, R Ghodbane, S. Mixed ion pair liquid chromatography method for the simultaneous assay of ascorbic acid, caffeine, chlorpheniramine maleate, dextromethorphan HBr monohydrate and paracetamol in Frenadol sachets. J.Pharm.Biomed.Anal., 1994,12, 85-90 [simultaneous caffeine, chlorpheniramine, dextromethorphan, vitamin C formulations] van der Veen, J. Eissens, A.C. Lerk, C.F. Controlled release of paracetamol from amylodextrin tablets In vitro and in vivo results. Pharm.Res., 1994, 11, 384-387 [plasma pharmacokinetics] Abounassif, M.A. Abdel-Moety, E.M. Gad-Kariem, R.A. HPLC-quantification of diethylamine saliqylate and methyl nicotinate in ointments. J.Liq.Chromatogn, 1992,15, 625-636 [formulations ointments simultabeous diethylamine salicylate, methyl nicotinate acetaminophen is IS simultaneous methyl paraben, propyl paraben... 

Lau, A.H. Chang, C.W. Schlesinger, P.K. Evaluation of a potential drug interaction between sucralfate and aspirin. Clin.Pharmacol.Ther, 1986, 39, 151-155 [plasma pharmacokinetics extracted metabolites, salicylic acid, salicyluric acid a-phenylcinnamic acid (IS) gradient column temp 30] Mamolo, M.G. Vio, L. Maurich, V. Higb-pressure liquid chromatographic analysis of paracetamol, caffeine and acetylsalicylic acid in tablets. Salicylic acid quantitation. Farmaco.[Prat]., 1985, 40, 111— 123 [tablets simultaneous ac etcuninophen, caffeine, phenazone, salicylic acid]... 

Kinney, C.D. Kelly, J.G. Liquid chromatographic determination of paracetamol and dextropropxyphene in plasma. J.Chromatogr., 1987, 419, 433-437 [verapamil (IS) electrochemical detection column temp 30 LOD 2 n mL pharmacokinetics]... 

Indometacin may attenuate the antihypertensive effect of losar-tan, valsartan, or other angiotensin II receptor antagonists. However, low-dose aspirin does not appear to alter the antihypertensive effect of losartan. No clinically relevant pharmacokinetic interactions occur between telmisartan and ibuprofen or paracetamol (acetaminophen), or between valsartan and indometacin. The combination of an NSAID and angiotensin II receptor antagonist can increase the risk of renal impairment and hyperkalaemia. 

Telmisartan 120 mg had no effect on the pharmacokinetics of paracetamol 1 g in a single-dose study in 12 healthy subjects. The pharmacokinetics of telmisartan were also unaffected by paracetamol, when compared with previous studies of telmisartan alone. ... 

Paracetamol 1 g was found to have no effect on the single-dose pharmacokinetics of alcohol in 12 healthy subjects. Another study found that blood-alcohol levels were raised by 1 g of paracetamol but this was not statistically significant. ... 

Stillings M, Havlik I, Chetty M, Clinton C, Schall R, Moodley I, Muir N, Little S. Comparison of the pharmacokinetic profiles of soluble aspirin and solid paracetamol tablets in fed and fasted volunteers. CurrMedRes Opin (2000) 6, 115-24. 

---