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Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients

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Abstract

Intravenous acetaminophen is a commonly used analgesic following surgery. The aims of this study were to determine the population pharmacokinetic profile of intravenous acetaminophen and its metabolites in adult surgical patients and to identify patient characteristics associated with acetaminophen metabolism in the postoperative period. 53 patients were included in the dataset; 28 were men, median age (range) 60 years (33–87), median weight (range) 74 kg (54–129). Patients received 1, 1.5 or 2 g of intravenous acetaminophen every 4–6 h. Plasma and urine samples were collected at various intervals for up to 6 days after surgery. Simultaneous modelling of parent acetaminophen and its metabolites was conducted in Phoenix® NLME™ to estimate pharmacokinetic parameters. The population mean estimate (CV%) for central (plasma) volume of distribution of parent acetaminophen (VC) was 13.9 (4.41) L, peripheral (tissue) volume of distribution (VT) was 50.9 (2.96) L, and intercompartmental clearance (Q) was 77.5 (9.29) L/h. The population mean (CV%) metabolic clearances for glucuronidation (CLPG) was 8.92 (3.25) L/h, sulfation (CLPS) was 0.903 (3.47) L/h, and oxidation (CLPO) was 0.533 (7.90) L/h. The population mean (CV%) urinary clearances of parent acetaminophen (CLRP) was 0.137 (5.46) L/h, acetaminophen glucuronide (CLRG) was 3.81 (6.71) L/h, acetaminophen sulfate (CLRS) was 3.13 (4.32) L/h, and acetaminophen cysteine + mercapturate (CLRO) was 3.51 (9.98) L/h. Age was found to be a significant covariate on the formation of acetaminophen glucuronide, and renal function (estimated as creatinine clearance) on the urinary excretion of acetaminophen glucuronide.

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Acknowledgments

The authors would like to thank the School of Pharmacy, University of Otago for Katie Owens’ PhD Scholarship and Pharsight (Mountain View, CA, USA) for the provision of Phoenix® NLME™.

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Authors and Affiliations

  1. School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand

    Katie H. Owens, Natalie J. Medlicott & Sree Sreebhavan

  2. University College Cork, Cork, Ireland

    Philip G. M. Murphy & Julia Kennedy

  3. Dunedin Hospital, Dunedin, New Zealand

    Mathew Zacharias & Neil Curran

  4. Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Mark Thompson-Fawcett & David M. Reith

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  1. Katie H. Owens
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Correspondence to Katie H. Owens.

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Owens, K.H., Murphy, P.G.M., Medlicott, N.J. et al. Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients. J Pharmacokinet Pharmacodyn 41, 211–221 (2014). https://doi.org/10.1007/s10928-014-9358-0

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