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Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects

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Abstract

Background and Objectives

Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified-release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test).

Methods

Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC–UV chiral method. Mean concentration–time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration–time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate.

Results

Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition.

Conclusions

R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration–time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes.

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References

  1. Brunton LL, Chabner BA, Knollmann BC, editors. Analgesic-antipyretic and anti-inflammatory agents: pharmacotherapy of gout. In: Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: Mc Graw-Hill Professional; 2010. p. 434–6.

  2. Furst DE, Ulrich RW, Prakash S. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. In: Katzung BG, Masters SB, Trevor AJ, editors. Basic and clinical pharmacology. 12th ed. New York: Mc Graw-Hill Professional; 2012. p. 636–8.

    Google Scholar 

  3. Jamali F, Brocks DR. Clinical pharmacokinetics of ketoprofen and its enantiomers. Clin Pharmacokinet. 1990;19:197–217.

    Article  CAS  PubMed  Google Scholar 

  4. Jamali F, Russell AS, Foster RT, Lemko C. Ketoprofen pharmacokinetics in humans: evidence of enantiomeric inversion and lack of interaction. J Pharm Sci. 1990;79:460–1.

    Article  CAS  PubMed  Google Scholar 

  5. Shi D, Jin Y, Tang Y, Hu H, Xu S, Yu L, Jiang H, Zeng S. Stereoselective binding of mexiletine and ketoprofen enantiomers with human serum albumin domains. Acta Pharmacol Sin. 2012;33:710–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barbanoj MJ, Antonijoan RM, Gich I. Clinical pharmacokinetics of dexketoprofen. Clin Pharmacokinet. 2001;40:245–62.

    Article  CAS  PubMed  Google Scholar 

  7. Foster RT, Jamali F. Stereoselective pharmacokinetics of ketoprofen in the rat: influence of route of administration. Drug Metab Dispos. 1988;16:623–6.

    CAS  PubMed  Google Scholar 

  8. Rudy C, Liu Y, Craig D, Hall D. Stereoselective inversion pharmacokinetics of (R)—ketoprofen in healthy volunteers. J Clin Pharmacol. 1998;38:3S–10S.

    Article  CAS  PubMed  Google Scholar 

  9. Grubb NG, Rudy DW, Brater DC, Hall SD. Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a “futile cycle” of elimination. Br J Clin Pharmacol. 1999;48:494–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mauleon D, Mis R, Ginesta J, Ortega E, Vilageliu J, Basi N, Carganico G. Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration. Chirality. 1994;6:537–42.

    Article  CAS  PubMed  Google Scholar 

  11. Mustonen K, Niemi A, Raekallio M, Heinonen M, Peltoniemi O, Palviainen M, Siven M, Peltoniemi M, Vainio O. Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs. Acta Vet Scand. 2012;54:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fagiolino P, Vazquez M, Alvariza S, Maldonado C, Ibarra M, Olano I. Antiepileptic drugs: energy-consuming processes governing drug disposition. Front Biosci. 2014;E6:387–96.

    Article  CAS  Google Scholar 

  13. Milne MD, Scribner BH, Crawford MA. Non-ionic diffusion and the excretion of weak acids and bases. Am J Med. 1958;24:709–29.

    Article  CAS  PubMed  Google Scholar 

  14. Ingraham RC, Visscher MB. Studies on the elimination of dyes in the gastric and pancreatic secretions, and inferences therefrom concerning the mechanisms of secretion of acid and base. J Gen Physiol. 1935;18:695–716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shohin IE, Kulinich JI, Ramenskaya GV, Abrahamsson B, Kopp S, Langguth P, Polli JE, Shah VP, Groot DW, Barends DM, Dressman JB. Biowaiver monographs for immediate-release solid oral dosage form: ketoprofen. J Pharm Sci. 2012;101:3593–603.

    Article  CAS  PubMed  Google Scholar 

  16. Hall JE, editor. Secretory functions of the alimentary tract. In: Guyton and Hall textbook of medical physiology. 12th ed. Philadelphia: Saunders; 2006. p. 799–802.

  17. He X, Lin R, He H, Sun M, Xiao D. Chiral separation of ketoprofen on a chirobiotic T column and its chiral recognition mechanisms. Chromatographia. 2012;75:1355–63.

    Article  CAS  Google Scholar 

  18. Kafková B, Bosáková Z, Tesařová E, Coufal P. Chiral separation of beta-adrenergic antagonists, profen non-steroidal anti-inflammatory drugs and chlorophenoxypropionic acid herbicides using teicoplanin as the chiral selector in capillary liquid chromatography. J Chromatogr A. 2005;1088:82–93.

    Article  PubMed  Google Scholar 

  19. Podzeck F, Newton JM, Wilding IR, Kenyon CJ. The effect of food on the gastrointestinal transit and systemic absorption of naproxen from a novel sustained release formulation. J Control Release. 1996;41:291–3.

    Article  CAS  Google Scholar 

  20. Magallanes L, Lorier M, Ibarra M, Guevara N, Vázquez M, Fagiolino P. Sex and food influence on intestinal absorption of ketoprofen gastroresistant formulation. Clin Pharmacol Drug Develop. 2015. doi:10.1002/cpdd.2008.

  21. Geisslinger G, Menzel S, Wissel K, Brune K. Pharmacokinetics of ketoprofen enantiomers after different doses of the racemate. Br J Clin Pharmacol. 1995;40:73–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tuo B, Wen G, Wei J, Liu X, Wang X, Zhang Y, Wu H, Dong X, Chow JYC, Vallon V, Dong H. Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. Gastroenterology. 2011;141:854–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vessey MP, Villard-Mackintosh LD, Painter R, Phil D. Oral contraceptives and pregnancy in relation to peptic ulcer. Contraception. 1992;46:349–57.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay

    Marianela Lorier, Laura Magallanes, Manuel Ibarra, Natalia Guevara, Marta Vázquez & Pietro Fagiolino

  2. Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay

    Marianela Lorier, Laura Magallanes, Manuel Ibarra, Natalia Guevara, Marta Vázquez & Pietro Fagiolino

Authors
  1. Marianela Lorier
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  2. Laura Magallanes
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  3. Manuel Ibarra
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  4. Natalia Guevara
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  5. Marta Vázquez
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  6. Pietro Fagiolino
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Corresponding author

Correspondence to Pietro Fagiolino.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

This investigation has not received any funding; however, the in vivo data were taken from a relative bioavailability study funded by Roemmers Laboratory, Uruguay.

Marianela Lorier received funds as fellow from the National Agency of Investigations and Innovation (ANII, as abbreviation of its Spanish spelling), Uruguay, under the code POS_NAC_2014_1_102512. All other authors have no conflicts of interest to declare.

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Lorier, M., Magallanes, L., Ibarra, M. et al. Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects. Eur J Drug Metab Pharmacokinet 41, 787–793 (2016). https://doi.org/10.1007/s13318-015-0313-2

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