Skip to main content

Advertisement

SpringerLink
Log in

The effect of operational stressors on ibuprofen pharmacokinetics

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine whether two of the major operational stressors associated with military missions in Afghanistan: dry heat and long durations of soldier patrol (SP), alter the pharmacokinetics of ibuprofen.

Methods

Thirteen healthy and physically fit participants (19–32 years) were randomized to a four-arm crossover study, as follows: Arm 4 consisted of a simulated 2.5 h SP on a treadmill set at 4.5 km/h, 2% incline (15-min walk/5-min rest cycle) in a climatic chamber set to 42°C, 9% relative humidity. Arm 3 was similar to arm 4 but at room temperature, and arms 1 and 2 were sham SP to 3 and 4, respectively. For the final 2.5 h, participants remained in a semi-supine position. Each participant orally administered one 400-mg Advil Liqui-Gel® capsule. Blood samples were drawn over time and analyzed for (R)-ibuprofen and (S)-plasma ibuprofen concentrations using UPLC/MS/MS. Concentration-time data were analyzed by compartmental methods.

Results

Exercise significantly decreased the t1/2abs (h) of (S)-ibuprofen (0.26 to 0.17; p = 0.015) and Tmax (h) for both (R)-ibuprofen (0.97 to 0.73; p = 0.008) and (S)-ibuprofen (1.13 to 0.84; p = 0.005). Values for tlag (h) also decreased with exercise for both (R)-ibuprofen (0.38 to 0.22; p = 0.005), and (S)-ibuprofen (0.39 to 0.23; p = 0.001).

Conclusions

Exercise stress had a significant impact on the absorption profile of (R) - and (S)-ibuprofen. Excessive self-administration rate and dose may not be due to the military operational stressors of heat and soldier presence patrol.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Knapik JJ, Reynolds KL, Harman E (2004) Soldier load carriage: historical, physiological, biomechanical, and medical aspects. Mil Med 169(1):45–56

    PubMed  Google Scholar 

  2. Sanders JW, Putnam SD, Frankart C et al (2005) Impact of illness and non-combat injury during Operations Iraqi Freedom and Enduring Freedom (Afghanistan). Am J Trop Med Hyg 73(4):713–719

    PubMed  Google Scholar 

  3. Radakovic SS, Maric J, Surbatovic M et al (2007) Effects of acclimation on cognitive performance in soldiers during exertional heat stress. Mil Med 172(2):133–136

    PubMed  Google Scholar 

  4. Lee EJ, Williams K, Day R et al (2004) Stereoselective disposition of ibuprofen enantiomers in man. 1985. Br J Clin Pharmacol 58(7):S759–S764

    Article  PubMed  CAS  Google Scholar 

  5. Kirchheiner J, Meineke I, Freytag G et al (2002) Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 72(1):62–75

    Article  PubMed  CAS  Google Scholar 

  6. Cheng H, Rogers JD, Demetriades JL et al (1994) Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm Res 11(6):824–830

    Article  PubMed  CAS  Google Scholar 

  7. Reichel C, Brugger R, Bang H et al (1997) Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen. Mol Pharmacol 51(4):576–582

    PubMed  CAS  Google Scholar 

  8. Hamman MA, Thompson GA, Hall SD (1997) Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54(1):33–41

    Article  PubMed  CAS  Google Scholar 

  9. Hao H, Wang G, Sun J (2005) Enantioselective pharmacokinetics of ibuprofen and involved mechanisms. Drug Metab Rev 37(1):215–234

    PubMed  CAS  Google Scholar 

  10. van den Broek MP, Groenendaal F, Egberts AC et al (2010) Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 49(5):277–294

    Article  PubMed  Google Scholar 

  11. Lenz TL, Lenz NJ, Faulkner MA (2004) Potential interactions between exercise and drug therapy. Sports Med 34(5):293–306

    Article  PubMed  Google Scholar 

  12. Wilmore JH, Costill DL (2005) Physiology of sport and exercise, 3rd edn. Human Kinetics, Champaign

    Google Scholar 

  13. American Society of Anesthesiologists (2012) ASA physical status classification system. http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System

  14. Portoles A, Vargas E, Burgos A et al (2002) Pharmacokinetic study of a new ibuprofen 600 mg plus codeine 30 mg combination versus ibuprofen or codeine alone in single oral doses in healthy volunteers. Clin Drug Invest 22(1):41–49

    Article  CAS  Google Scholar 

  15. Szeitz A, Edginton AN, Peng HT et al (2010) A validated enantioselective assay for the determination of ibuprofen in human plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). AJAC 1(2):47–58

    Article  CAS  Google Scholar 

  16. Ganio MS, Brown CM, Casa DJ et al (2009) Validity and reliability of devices that assess body temperature during indoor exercise in the heat. J Athl Train 44(2):124–135

    Article  PubMed  Google Scholar 

  17. Borg GA (1982) Psychophysical bases of perceived exertion. Med Sci Sports Exerc 14(5):377–381

    PubMed  CAS  Google Scholar 

  18. Gagge AP, Stolwijk JA, Hardy JD (1967) Comfort and thermal sensations and associated physiological responses at various ambient temperatures. Environ Res 1(1):1–20

    Article  PubMed  CAS  Google Scholar 

  19. Yamaoka K, Nakagawa T, Uno T (1978) Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6(2):165–175

    PubMed  CAS  Google Scholar 

  20. Selkirk GA, McLellan TM, Wong J (2006) The impact of various rehydration volumes for firefighters wearing protective clothing in warm environments. Ergonomics 49(4):418–433

    Article  PubMed  CAS  Google Scholar 

  21. Belding HS (1970) The search for a universal heat stress index. In: Hardy JD, Gagge AP, Stolwijk JAS (ed) Physiological and behavioral temperature regulation. Thomas, Springfield, IL, pp 193–202

  22. Selkirk GA, McLellan TM (2001) Influence of aerobic fitness and body fatness on tolerance to uncompensable heat stress. J Appl Physiol 91(5):2055–2063

    PubMed  CAS  Google Scholar 

  23. Cheung SS, Petersen SR, McLellan TM (2010) Physiological strain and countermeasures with firefighting. Scand J Med Sci Sports 20(Suppl 3):103–16

    Article  PubMed  Google Scholar 

  24. Haller CA, Duan M, Jacob P III et al (2008) Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol 65(6):833–840

    Article  PubMed  Google Scholar 

  25. Aslaksen A, Aanderud L (1980) Drug absorption during physical exercise. Br J Clin Pharmacol 10(4):383–385

    PubMed  CAS  Google Scholar 

  26. van Nieuwenhoven MA, Brouns F, Brummer RJ (2004) Gastrointestinal profile of symptomatic athletes at rest and during physical exercise. Eur J Appl Physiol 91(4):429–434

    Article  PubMed  Google Scholar 

  27. Ollerenshaw KJ, Norman S, Wilson CG et al (1987) Exercise and small intestinal transit. Nucl Med Commun 8(2):105–110

    Article  PubMed  CAS  Google Scholar 

  28. Leiper JB, Nicholas CW, Ali A et al (2005) The effect of intermittent high-intensity running on gastric emptying of fluids in man. Med Sci Sports Exerc 37(2):240–247

    Article  PubMed  Google Scholar 

  29. Cammack J, Read NW, Cann PA et al (1982) Effect of prolonged exercise on the passage of a solid meal through the stomach and small intestine. Gut 23(11):957–961

    Article  PubMed  CAS  Google Scholar 

  30. Moore JG, Datz FL, Christian PE (1990) Exercise increases solid meal gastric emptying rates in men. Dig Dis Sci 35(4):428–432

    Article  PubMed  CAS  Google Scholar 

  31. Lambert GP, Boylan M, Laventure JP et al (2007) Effect of aspirin and ibuprofen on GI permeability during exercise. Int J Sports Med 28(9):722–726

    Article  PubMed  CAS  Google Scholar 

  32. Nerella NG, Block LH, Noonan PK (1993) The impact of lag time on the estimation of pharmacokinetic paramters. I. One-compartment open model. Pharm Res 10:1031–1034

    Article  PubMed  CAS  Google Scholar 

  33. Ylitalo P, Hinkka H, Neuvonen PJ (1977) Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole. Eur J Clin Pharmacol 12(5):367–373

    Article  PubMed  CAS  Google Scholar 

  34. Stromberg C, Vanakoski J, Olkkola KT et al (1992) Exercise alters the pharmacokinetics of midazolam. Clin Pharmacol Ther 51(5):527–532

    Article  PubMed  CAS  Google Scholar 

  35. Rehrer NJ, Smets A, Reynaert H et al (2001) Effect of exercise on portal vein blood flow in man. Med Sci Sports Exerc 33(9):1533–1537

    Article  PubMed  CAS  Google Scholar 

  36. Rowell LB, Blackmon JR, Martin RH et al (1965) Hepatic clearance of indocyanine green in man under thermal and exercise stresses. J Appl Physiol 20(3):384–394

    PubMed  CAS  Google Scholar 

  37. Sweeney GD (1981) Drugs–some basic concepts. Med Sci Sports Exerc 13(4):247–251

    Article  PubMed  CAS  Google Scholar 

  38. Koda M, Komori S, Nagami M et al (1995) Effects of bathing in hot water on portal hemodynamics in healthy subjects and in patients with compensated liver cirrhosis. Intern Med 34(7):628–631

    Article  PubMed  CAS  Google Scholar 

  39. Lötsch J, Muth-Selbach U, Tegeder I et al (2001) Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate. Br J Clin Pharmacol 52(4):387–98

    Article  PubMed  Google Scholar 

  40. Pavliv L, Voss B, Rock A (2011) Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults. Am J Health-Syst Pharm 68:47–51

    Article  PubMed  CAS  Google Scholar 

  41. Tan SC, Patel BK, Jackson SH et al (2002) Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers. Xenobiotica 32(8):683–697

    Article  PubMed  CAS  Google Scholar 

  42. Sidhu P, Peng H, Cheung B et al (2011) Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically-based pharmacokinetic modeling approach. Can J Physiol Pharmacol 89(5):365–382

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the technical staff for their outstanding support: Mrs. Debbie Kerrigan-Brown, Mr. Kevin Hofer, Mr. Jan Pope, Mr. Doug Saunders, Mrs. Ingrid Smith, and Mr. Juan Carlos Bernal. Thank you to all who participated as volunteers. A special thank you to LCol Cliff Trollope for his invaluable support and to his troops from the Royal Regiment of Canada (Fort York Armoury) for their participation. The authors also thank Dr. Peter Tikuisis for his valuable comments on data analysis of the pilot study. This study was funded by Defence Research and Development Canada (DRDC).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Defence Research and Development Canada Toronto, 1133 Sheppard Ave. West, Toronto, ON, Canada, M3K 2C9

    Cathy Boscarino, Henry Peng & Bob Cheung

  2. School of Pharmacy, University of Waterloo, 200 University Ave. West, Waterloo, ON, Canada

    Andrea N. Edginton

  3. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada, V6T 1Z3

    K. Wayne Riggs & András Szeitz

Authors
  1. Cathy Boscarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea N. Edginton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henry Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Wayne Riggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. András Szeitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bob Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cathy Boscarino.

Appendix: pilot study

Appendix: pilot study

An 8-h pilot study on arm 4 (n = 4) was conducted to determine if the elimination half-life (t1/2_elim) and area under the plasma concentration-time curve (AUC0→∞) could be reliably extrapolated from a 5-h mark time point for the study.

Figure 3 shows the geometric means of (R)- and (S)-ibuprofen plasma concentrations as a function of time. The two pharmacokinetics parameters were calculated using the add-ins of pharmacokinetics functions in Microsoft Office Excel 2003. As shown in Fig. 3, the data from 2 to 4 h and from 2 to 8 h for each individual were used for the calculation of t1/2, respectively, and the data from 0 to 4 h and from 0 to 8 h were included for the calculation of AUC0→∞, respectively. Paired t tests were conducted to compare the 4- and 8-h results. Table 3 summarizes the results and presents the p values for comparison between the 4- and 8-h results. The elimination half-life and area under the plasma concentration-time curve from the 4-h calculation did not differ significantly from the 8-h group due to the large individual variation. Hence, t1/2 and AUC0→∞can be extrapolated without significant error.

Fig. 3
figure 3

Plasma concentration vs. time profiles for the 8-h pilot study (arm 4) for (R)-ibuprofen (squares) and (S)-ibuprofen (circles). One 400-mg Advil Liqui-Gel® capsule was administered orally immediately prior to the start of the arm. Data are presented as geometric mean ± SD

Full size image
Table 3 Summary of individual pharmacokinetics parameters (AUC0→∞) and t1/2 from the pilot study
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boscarino, C., Edginton, A.N., Peng, H. et al. The effect of operational stressors on ibuprofen pharmacokinetics. Eur J Clin Pharmacol 69, 31–41 (2013). https://doi.org/10.1007/s00228-012-1307-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1307-5

Keywords

Search

Navigation