Abstract
Background and Objectives
Intravenous paracetamol (N-acetyl-paraminophenol, acetaminophen) is a widely used nonopioid analgesic which has become popular in the treatment of pain in many patient groups, including the elderly. Although intravenous paracetamol has been studied widely in clinical analgesia studies, there is little information on its pharmacokinetics in the elderly. We designed this study to determine the pharmacokinetics of intravenous paracetamol in very old patients and to compare them with that of younger patients. We also considered the effect of adenosine triphosphate-binding cassette G2 protein (ABCG2) genotype and renal function on paracetamol pharmacokinetics in these patients.
Methods
We compared the pharmacokinetics of intravenous paracetamol in four groups of ten patients, aged 20–40, 60–70, 70–80 and 80–90 years, undergoing orthopaedic surgery. Paracetamol 1000 mg was given by infusion over 15 minutes. Plasma concentrations of paracetamol and its glucuronide and sulphate conjugates were measured for 24 hours with a high-performance liquid chromatographic method and ABCG2 genotype was determined. Glomerular filtration rate (GFR) was estimated from age, sex and serum creatinine of the patient.
Results
In the group aged 80–90 years, the mean value of the area under the plasma concentration-time curve extrapolated to infinity (AUC∞) of paracetamol was 54–68% higher than in the two youngest groups. Paracetamol clearance showed a statistically significant dependence on age group, whereas volume of distribution during elimination and elimination half-life were associated with age group and sex, respectively. Based on mean AUC∞ of paracetamol glucuronide and paracetamol sulphate, the oldest patients had 1.3- to 1.5-fold greater exposure to these metabolites than patients aged 20–40 years. ABCG2 genotype did not affect paracetamol pharmacokinetics. There was a linear correlation between the values of AUC∞ of paracetamol, its glucuronide and sulphate metabolites and GFR.
Conclusion
Age and sex are important factors affecting the pharmacokinetics of paracetamol. The higher the age of the patient, the higher is the exposure to paracetamol. Female sex is associated with increased paracetamol concentrations but ABCG2 genotype does not seem to affect paracetamol pharmacokinetics.
Trial registration number (EudraCT): 2006-001917-14
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References
Hyllested M, Jones S, Pedersen JL, et al. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002; 88: 199–214
Elia N, Lysakowski C, Tramér MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Anesthesiology 2005; 103: 1296–304
Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005; 94: 505–13
Sinatra RS, Jahr JS, Reynolds LW, et al. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) of pain management after major orthopedic surgery. Anesthesiology 2005; 102: 822–31
Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35: 49–64
Butler JM, Begg EJ. Free drug metabolic clearance in elderly people. Clin Pharmacokinet 2008; 47: 297–321
White M, Kenny GN, Schraag S. Use of target controlled infusion to derive age and gender covariates for propofol clearance. Clin Pharmacokinet 2008; 47: 119–27
Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009; 41: 67–76
Miller RP, Roberts RJ, Fisher LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19: 284–94
Hardwick LJ, Velamakanni S, van Veen HW. The emerging pharmaco-therapeutic significance of the breast cancer resistance protein (ABCG2). Br J Pharmacol 2007; 151: 163–74
Kondo C, Suzuki H, Itoda M, et al. Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res 2004; 21: 1895–903
Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139: 137–47
Vertzoni MV, Archontaki HA, Galanopoulou P. Development and optimization of a reversed-phase high-performance liquid chromatographic method for the determination of acetaminophen and its major metabolites in rabbit plasma and urine after a toxic dose. J Pharmaceut Biomed 2003; 32: 487–93
Keskitalo JE, Zolk O, Fromm MF, et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2009; 86: 197–203
Triggs EJ, Nation RL, Long A, et al. Pharmacokinetics in the elderly. Eur J Clin Pharmacol 1975; 8: 55–62
Miners JO, Penhall R, Robinson RA, et al. Comparison of paracetamol metabolism in young adult and elderly males. Eur J Clin Pharmacol 1988; 35: 157–60
Briant RH, Dorrington RE, Cleal J, et al. The rate of acetaminophen metabolism in the elderly and the young. J Am Geriatr Soc 1976; 24: 359–61
Divoll M, Abernethy DR, Ameer B, et al. Acetaminophen kinetics in the elderly. Clin Pharmacol Ther 1982; 31: 151–6
Wynne HA, Cope LH, Herd B, et al. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990; 19: 419–24
Zamek-Gliszczynski MJ, Nezasa K, Tian X, et al. The important role of bcrp (abcg2) in the biliary excretion of sulphate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in mice. Mol Pharmacol 2006; 70: 2127–33
Prescott LF, Speirs GC, Critchley JA, et al. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur J Clin Pharmacol 1989; 36: 291–7
Bannwarth B, Pehourcq F, Lagrange F, et al. Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain. J Rheumatol 2001; 28: 182–4
Electronic Medicines Compendium UK. Perfalgan 10mg/mL solution for infusion: summary of product characteristics [online]. Available from URL: http://emc.medicines.org.uk/medicine/14288/SPC/Perfalgan%2010mg/ml%20Solution%20for%20Infusion/ [Accessed 2010 Nov 8]
Sweetman S, editor. Martindale: the complete drug reference [electronic version]. London: Pharmaceutical Press, 2006 Sep 1
Kaplowitz N. Acetaminophen hepatoxicity: what do we know, what don’t we know, and what do we do next? Hepatology 2004; 40: 23–6
Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296: 87–93
Manyike PT, Kharasch ED, Kalhorn TF, et al. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000; 67: 275–82
Gelotte CK, Aulier JF, Lynch JM, et al. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther 2007; 81: 840–8
American Academy of Pediatrics Committee on Drugs. Acetaminophen toxicity in children. Pediatrics 2001; 108: 1020–4
Acknowledgements
This study was supported by the Turku University Hospital Research Fund #13821, Turku University Foundation (Turku, Finland) and the Sigrid Jusélius Foundation (Helsinki, Finland). Klaus T. Olkkola is a member of the Advisory Board of MSD, Finland. All other authors have no conflicts of interest that are directly relevant to the content of this study.
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Liukas, A., Kuusniemi, K., Aantaa, R. et al. Pharmacokinetics of Intravenous Paracetamol in Elderly Patients. Clin Pharmacokinet 50, 121–129 (2011). https://doi.org/10.2165/11537240-000000000-00000
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DOI: https://doi.org/10.2165/11537240-000000000-00000