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

  • Katie H. Owens
  • Philip G. M. Murphy
  • Natalie J. Medlicott
  • Julia Kennedy
  • Mathew Zacharias
  • Neil Curran
  • Sree Sreebhavan
  • Mark Thompson-Fawcett
  • David M. Reith
Original Paper

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.

Keywords

Acetaminophen Analgesia Surgery Population pharmacokinetics Drug metabolism Phoenix NLME 

Notes

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™.

Supplementary material

10928_2014_9358_MOESM1_ESM.docx (14.2 mb)
Supplementary material 1 (DOCX 14545 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Katie H. Owens
    • 1
  • Philip G. M. Murphy
    • 2
  • Natalie J. Medlicott
    • 1
  • Julia Kennedy
    • 2
  • Mathew Zacharias
    • 3
  • Neil Curran
    • 3
  • Sree Sreebhavan
    • 1
  • Mark Thompson-Fawcett
    • 4
  • David M. Reith
    • 4
  1. 1.School of PharmacyUniversity of OtagoDunedinNew Zealand
  2. 2.University College CorkCorkIreland
  3. 3.Dunedin HospitalDunedinNew Zealand
  4. 4.Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand

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