Influence of the Time of Intravenous Administration of Paracetamol on its Pharmacokinetics and Ocular Disposition in Rabbits

  • 154 Accesses

  • 1 Citations


Background and Objectives

Paracetamol is one of the most common analgesics and antipyretics applied in health care. The aim of the study was to investigate the influence of the time-of-day administration on the paracetamol pharmacokinetics and its penetration into aqueous humour (AH).


Rabbits were divided into three groups: I—receiving paracetamol at 08.00 h, II—receiving paracetamol at 16.00 h, and III—receiving paracetamol at 24.00 h. Paracetamol was administered intravenously at a single dose of 35 mg/kg. The concentrations of paracetamol and its metabolite (paracetamol glucuronide) in the plasma, as well as in AH were measured with the validated HPLC–UV method.


No significant differences in the pharmacokinetic parameters of paracetamol was observed. When the drug was administered at 24.00 h,  elimination half-life (t 1/2kel) of paracetamol glucuronide was longer than when the drug was administered 08.00 h (P = 0.0193). In addition, a statistically significant increase in the paracetamol glucuronide/paracetamol ratio was observed when the drug was administered at 08.00 vs. 16.00 h (P ≤ 0.0001) and 24.00 h (P ≤ 0.0001).


There was no chronobiological effect on the pharmacokinetic parameters of paracetamol.

This is a preview of subscription content, log in to check access.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Bruguerolle B. Chronopharmacokinetics. Current status. Clin Pharmacokinet. 1998;35:83–94.

  2. 2.

    Misiołek H, Cettler M, Woroń J, Wordliczek J, Dobrogowski J, Mayzner-Zawadzka E, et al. The 2014 guidelines for post-operative pain management. Anaesthesiol Intensive Ther. 2014;46:221–44.

  3. 3.

    Guidelines for Pain Management. Programmes for adults. An evidence-based review prepared on behalf of the British Pain Society. The British Pain Society November 2013. To be reviewed October 2018. Accessed 5 July 2016.

  4. 4.

    Beal BR, Wallace MS. An overview of pharmacologic management of chronic pain. Med Clin North Am. 2016;100:65–79.

  5. 5.

    Kolawole JA, Chuwak PD, Okeniyi SO. Chronopharmacokinetics of acetaminophen in healthy human volunteers. Eur J Drug Metab Pharmacokinet. 2002;27:199–202.

  6. 6.

    Porela-Tiihonen S, Kaarniranta K, Kokki M, Purhonen S, Kokki H. A prospective study on postoperative pain after cataract surgery. Clin Ophthalmol. 2013;7:1429–35.

  7. 7.

    Harding JJ, van Heyningen R. Drugs, including alcohol, that act as risk factors for cataract, and possible protection against cataract by aspirin-like analgesics and cyclopenthiazide. Br J Ophtalmol. 1988;72:809–14.

  8. 8.

    Bienert A, Kamińska A, Olszewski J, Gracz J, Grabowski T, Wolc A, Grześkowiak E. Pharmacokinetics and ocular disposition of paracetamol and paracetamol glucuronide in rabbits with diabetes mellitus induced by alloxan. Pharmacol Rep. 2012;64:421–7.

  9. 9.

    Shahidullah M, Al-Malki WH, Delamere NA. Mechanism of aqueous humor secretion, its regulation and relevance to glaucoma. In Rumelt S, editor. Glaucoma—basic and clinical concepts. InTech. 2011. Accessed 1 Mar 2016.

  10. 10.

    Toda R, Kawazu K, Oyabu M, Miyazaki T, Kiuchi Y. Comparison of drug permeabilities across the blood-retinal barrier, blood-aqueous humor barrier, and blood-brain barrier. J Pharm Sci. 2011;100:3904–11.

  11. 11.

    Slosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente ML, Vanderah TW, et al. Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol. 2013;84:774–86.

  12. 12.

    Fujii S, Setoguchi C, Kawazu K, Hosoya K. Impact of P-glycoprotein on blood-retinal barrier permeability: comparison of blood-aqueous humor and blood-brain barrier using mdr1a knockout rats. Invest Ophthalmol Vis Sci. 2014;55:4650–8.

  13. 13.

    Portaluppi F, Smolensky MH, Touitou Y. Ethics and methods for biological rhythm research on animals and human beings. Chronobiol Int. 2010;27:1911–29.

  14. 14.

    Bélanger PM, Lalande M, Doré F, Labrecque G. Time-dependent variations in the organ extraction ratios of acetaminophen in rat. J Pharmacokinet Biopharm. 1987;15:133–43.

  15. 15.

    Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesth Analg. 2005;101:90–6.

  16. 16.

    Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med. 2011;12:961–81.

  17. 17.

    Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund LA. Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery. Br J Anaesth. 2005;94:642–8.

  18. 18.

    Koh W, Nguyen KP, Jahr JS. Intravenous non-opioid analgesia for peri- and postoperative pain management: a scientific review of intravenous acetaminophen and ibuprofen. Korean J Anesthesiol. 2015;68:3–12.

  19. 19.

    Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12:250–75.

  20. 20.

    Levi F, Schibler U. Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol. 2007;47:593–628.

  21. 21.

    Junker U, Wirz S. Chronobiology: influence of circadian rhythms on the therapy of severe pain. J Oncol Pharm Pract. 2010;16:1–87.

  22. 22.

    Kamali F, Thomas SH, Ferner RE. Paracetamol elimination in patients with non-insulin dependent diabetes mellitus. Br J Clin Pharmac. 1993;35:58–61.

  23. 23.

    Malan J, Moncrieff J, Bosch E. Chronopharmakokinetics of paracetamol in normal subjects. Br J Clin Pharmac. 1985;19:843–5.

  24. 24.

    Ngong JM, Waring RH. Circadian rhythms of paracetamol metabolism in healthy subjects; a preliminary report. Drug Metabol Drug Interact. 1994;11:317–30.

  25. 25.

    Johnson BP, Walisser JA, Liu Y, Shen AL, McDearmon EL, Moran SM, McIntosh BE, Vollrath AL, Schook AC, Takahashi JS, Bradfield CA. Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. Proc Natl Acad Sci USA. 2014;111:18757–62.

  26. 26.

    DeBruyne JP, Weaver DR, Dallmann R. Clock gene mPer2 functions in diurnal variation of acetaminophen induced hepatotoxicity in mice. Exp Toxicol Pathol. 2011;63:581–5.

  27. 27.

    Kim YC, Lee SJ. Temporal variation in hepatotoxicity and metabolism of acetaminophen in mice. Toxicology. 1998;128:53–61.

  28. 28.

    Schnell RC, Bozigian HP, Davies MH, Merrick BA, Johnson KL. Circadian rhythm in acetaminophen toxicity: role of nonprotein sulfhydryls. Toxicol Appl Pharmacol. 1983;71:353–61.

  29. 29.

    Shively CA, Vesell ES. Temporal variations in acetaminophen and phenacetin half-life in man. Clin Pharmacol Ther. 1975;18:413–24.

  30. 30.

    Kamali F, Fry JR, Bell GD. Temporal variations in paracetamol absorption and metabolism in man. Xenobiotica. 1987;17:635–41.

  31. 31.

    Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007;81:840–8.

  32. 32.

    Mutlib AE, Goosen TC, Bauman JN, Williams JA, Kulkarni S, Kostrubsky S. Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2006;19:701–9.

  33. 33.

    Wawrzyniak-Andrys I, Jabłecka A. Chronobiology, chronopharmacology on medicine (Part II). Farmacja Współczesna. 2008;1:94–108.

  34. 34.

    Toris CB. Aqueous humor dynamics in the healthy human eye. In: Shaarawy TM, Sherwood MB, Hitchings RA, Crowston JG, editors. Glaucoma, vol. 1, 2nd edn. Philadelphia: Elsevier Saunders; 2015. p. 47.

  35. 35.

    Sobańska K, Karbownik A, Szałek E, Płotek W, Grabowski T, Szewczyk A, Marcinkowska D, Połom W, Matuszewski M, Grześkowiak E. The influence of time-of-day administration of sunitinib on the penetration through the blood-brain and blood-aqueous barriers in rabbits. Eur Rev Med Pharmacol Sci. 2016;20:166–73.

  36. 36.

    Romanelli L, Valeri P, Morrone LA, Pimpinella G. Ocular disposition of acetaminophen and its metabolites following intravenous administration in rabbits. J Ocul Pharmacol. 1991;7:339–50.

  37. 37.

    Yoshida Y, Nakazato K, Takemori K, Kobayashi K, Sakamoto A. The influences of propofol and dexmedetomidine on circadian gene expression in rat brain. Brain Res Bull. 2009;79:441–4.

  38. 38.

    Ohe Y, Iijima N, Kadota K, Sakamoto A, Ozawa H. The general anesthetic sevoflurane affects the expression of clock gene mPer2 accompanying the change of NAD + level in the suprachiasmatic nucleus of mice. Neurosci Lett. 2011;490:231–6.

  39. 39.

    Boscariol R, Gilron I, Orr E. Chronobiological characteristic of postoperative pain: diurnal variation of both static and dynamic pain and effects of analgesic therapy. Can J Anesth. 2007;54:696–704.

Download references

Author information

Correspondence to Włodzimierz Płotek.

Ethics declarations

Conflict of interest

The authors Agnieszka Karbownik, Agnieszka Bienert, Włodzimierz Płotek, Tomasz Grabowski, Magdalena Cerbin-Koczorowska, Anna Wolc, Edmund Grześkowiak declare that they have no conflict of interests. The authors disclose no financial, consulting, and personal relationships with people or organizations that could be perceived by readers as biasing the authors’ work.


The financial support was provided by the Poznan University of Medical Sciences only.


The welfare of animals used for was respected. Authors adhered to ethical guidelines provided by Portaluppi, who recommended ethical criteria for biological rhythm research on animals proposed in Chronobiology International (Chronobiol Int. 2010;27:1911–29). The experiment protocol was approved by the local Ethics Committee for Animal Research. All procedures were performed in accordance with the Polish regulations for the handlings and use of laboratory animals (Nr of consent: 01/2015). The appropriate written consent from the local Ethics Committee for Animal Research is available if requested. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Karbownik, A., Bienert, A., Płotek, W. et al. Influence of the Time of Intravenous Administration of Paracetamol on its Pharmacokinetics and Ocular Disposition in Rabbits. Eur J Drug Metab Pharmacokinet 42, 489–498 (2017).

Download citation


  • Paracetamol
  • Sunitinib
  • Dexmedetomidine
  • Aqueous Humour
  • Pain Treatment