Open Access Peer-reviewed Research Article

Main Article Content

Hawsar Othman Mohamed
Attila Almási
Pal Perjesi corresponding author

Abstract

Diabetic complications are mostly due to hyperglycemia. Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics. An in vivo intestinal perfusion model was used to investigate how experimental hyperglycemia affects intestinal elimination and biliary excretion of ibuprofen enantiomers in the rat. Experimental diabetes was induced by intravenous (i.v.) administration of streptozotocin. The intestinal perfusion medium contained 250 µM racemic ibuprofen. A validated isocratic chiral HPLC method with UV detection was developed to determine the amount of the two enantiomers in the intestinal perfusate and the bile. The results indicated that experimental diabetes doesn’t cause a statistically significant difference in the disappearance of ibuprofen enantiomers from the small intestine. Analysis of the bile samples detected only the (S)-IBP enantiomer. Excretion of the ibuprofen enantiomer to the bile decreased in experimental diabetes. The observed changes can affect the pharmacokinetics of drugs administered in hyperglycemic individuals.

Keywords
streptozotocin, hyperglycaemia, (S)-ibuprofen, biliary excretion

Article Details

Author Biography

Pal Perjesi, Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Pécs, Pécs, Hungary

The editor-in-chief of Journal of Pharmaceutical and Biopharmaceutical Research.

Supporting Agencies
This study was supported by the European Union and co-financed by the European Social Fund (EFOP-3.6.1.-16-2016-00004). The financial support is highly appreciated.
How to Cite
Mohamed, H. O., Almási, A., & Perjesi, P. (2022). Effect of experimental hyperglycemia on intestinal elimination and biliary excretion of ibuprofen enantiomers in hyperglycemic rats. Journal of Pharmaceutical and Biopharmaceutical Research, 4(2), 283-295. https://doi.org/10.25082/JPBR.2022.02.001

References

  1. Mazaleuskaya LL, Theken KN, Gong L, et al. PharmGKB summary: Ibuprofen pathways. Pharmacogenetics and Genomics, 2015, 25: 96-106. https://doi.org/10.1097/FPC.0000000000000113
  2. Rudy AC, Knight PM, Brater DC, et al. Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen. The Journal of Pharmacology and Experimental Therapeutics, 1991, 259: 1133-1139. https://doi.org/10.0000/PMID1762067
  3. Brocks D and Jamali F. The pharmacokinetics of ibuprofen in humans and animals. In: Rainsford KD (ed), Ibuprofen. A critical bibliographic review. Taylor & Francis, London, 1999, 89-142.
  4. Jeffrey P, Tucker GT, Bye A, et al. The site of inversion of R(-)-ibuprofen: studies using rat in situ isolated perfused intestine/liver preparations. Journal of Pharmacy and Pharmacology, 1991, 43: 715-720. https://doi.org/10.1111/j.2042-7158.1991.tb03464.x
  5. Jamali F, Mehvar R, Russell AS, et al. Human pharmacokinetics of ibuprofen enantiomers following different doses and formulations: intestinal chiral inversion. Journal of Pharmaceutical Sciences, 1992, 81: 221-225. https://doi.org/10.1002/jps.2600810306
  6. Keep DR, Sidelmann UG and Hansen SH. Isolation and characterization of major phase I and II metabolites of ibuprofen. Pharmaceutical Research, 1997, 14: 676-680. https://doi.org/10.1023/A:1012125700497
  7. Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology, 2009, 17: 275-342. https://doi.org/10.1007/s10787-009-0016-x
  8. Kovács NP, Almási A, Garai K, et al. Investigation of intestinal elimination and biliary excretion of ibuprofen in hyperglycemic rats. The Canadian Journal of Physiology and Pharmacology, 2019, 97: 1080-1089. https://doi.org/10.1139/cjpp-2019-0164
  9. Fischer E, Almási A, Bojcsev S, et al. Effect of experimental diabetes and insulin replacement on intestinal metabolism and excretion of 4-nitrophenol in rats. The Canadian Journal of Physiology and Pharmacology, 2015, 93: 459-464. https://doi.org/10.1139/cjpp-2015-0065
  10. Almási A, Perjési P and Fischer E. The relative importance of the small intestine and the liver in Phase II metabolic transformations and elimination of p-nitrophenol administered in different doses in the rat. Scientia Pharmaceutica, 2020, 88: 512020. https://doi.org/10.3390/scipharm88040051
  11. Klaassen CD. Bile flow and bile composition during bile acid depletion and administration. Canadian journal of physiology and pharmacology, 1974, 52: 334-348. https://doi.org/10.1139/y74-045
  12. Bonato PS, Del Lama MPFM and de Carvalho R. Enantioselective determination of ibuprofen in plasma by high-performance liquid chromatography–electrospray mass spectrometry. Journal of Chromatography B, 2003, 796: 413-420. https://doi.org/10.1016/j.jchromb.2003.08.031
  13. Kromasil Application Note, n.d., viewed September 28, 2022. https://www.kromasil.com/applications/view.php?app=c0128
  14. European legislation (Directive 2010/63/E.U.). viewed September 28, 2022. https://eur-lex.europa.eu/eli/dir/2010/63/oj
  15. Hungarian Government regulation (40/2013., II. 14.) viewed September 28, 2022. https://www.fao.org/faolex/results/details/en/c/LEX-FAOC124420
  16. Legen I, Zakelj S and Kristl A. Polarised transport of monocarboxylic acid type drugs across rat jejunum in vitro: the effect of mucolysis and ATP-depletion. International Journal of Pharmaceutics, 2003, 256: 161-166. https://doi.org/10.1016/s0378-5173(03)00073-5
  17. Liu H, Xu X, Yang Z, et al. Impaired function and expression of P-glycoprotein in blood-brain barrier of streptozotocin-induced diabetic rats. Brain Research, 2006, 1123: 245-252. https://doi.org/10.1016/j.brainres.2006.09.061
  18. Nawa A, Fujita Hamabe W and Tokuyama S. Inducible nitric oxide synthase-mediated decrease of intestinal P-glycoprotein expression under streptozotocin-induced diabetic conditions. Life Sciences, 2010, 86: 402-409. https://doi.org/10.1016/j.lfs.2010.01.009
  19. Zhang L, Lu L, Jin S, et al. Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats. Acta Pharmacologica Sinica, 2011, 32: 956-966. https://doi.org/10.1038/aps.2011.33
  20. Drozdzik M, Czekawy I, Oswald S, et al. Intestinal drug transporters in pathological states: an overview. Pharmacological Reports, 2020, 72: 1173-1194. https://doi.org/10.1007/s43440-020-00139-6
  21. Angelini A, Lezzi M, di Febbo C, et al. Reversal of P-glycoprotein-mediated multidrug resistance in human sarcoma MES-SA/Dx-5 cells by nonsteroidal anti-inflammatory drugs. Oncology Reports, 2008, 20: 731-735. https://doi.org/10.3892/or_00000067
  22. Klaassen CD and Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacological Reviews, 2010, 62(1): 1-96. https://doi.org/10.1124/pr.109.002014
  23. Burckhardt G. Drug transport by Organic Anion Transporters (OATs). Pharmacology & Therapeutics, 2012, 136: 106-130. https://doi.org/10.1016/j.pharmthera.2012.07.010
  24. Cha SH, Sekine T, Fukushima JI, et al. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Molecular Pharmacology, 2001, 59: 1277-1286. https://doi.org/10.1124/mol.59.5.1277
  25. Kobayashi Y, Ohshiro N, Sakai R, et al. Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). Journal of Pharmacy and Pharmacology, 2005, 57: 573-578. https://doi.org/10.1211/0022357055966
  26. Nigam SK, Bush KT, Martovetsky G, et al. The organic anion transporter (OAT) family: A systems biology perspective. Physiological Reviews, 2015, 95: 83-123. https://doi.org/10.1152/physrev.00025.2013
  27. Fork C, Bauer T, Golz S, et al. OAT2 catalyses efflux of glutamate and uptake of orotic acid. The Biochemical Journal, 2011, 436: 305-312. https://doi.org/10.1042/BJ20101904
  28. Kimoto E, Mathialagan S, Tylaska L, et al. Organic anion transporter 2–mediated hepatic uptake contributes to the clearance of high-permeability–low-molecular-weight acid and zwitterion drugs: Evaluation using 25 drugs. The Journal of Pharmacology and Experimental Therapeutics, 2018, 367: 322-334. https://doi.org/10.1124/jpet.118.252049
  29. Kindla J, Müller F, Mieth M, et al. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metabolism and Disposition, 2011, 39: 1047-1053. https://doi.org/10.1124/dmd.110.037622
  30. Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clinical Pharmacokinetics, 1998, 34: 101-154. https://doi.org/10.2165/00003088-199834020-00002
  31. Schneider HT, Nuernberg B, Dietzel K, et al. Biliary elimination of non-steroidal anti-inflammatory drugs in patients. British Journal of Clinical Pharmacology, 1990, 29: 127-131. https://doi.org/10.1111/j.1365-2125.1990.tb03613.x
  32. Anger GJ, Magomedova L and Piquette-Miller M. Impact of acute streptozotocin-induced diabetes on ABC transporter expression in rats. Chemistry and Biodiversity, 2009, 6: 1943-1959. https://doi.org/10.1002/cbdv.200900053
  33. Jetter A and Kullak-Ublick GA. Drugs and hepatic transporters: A review. Pharmacological Research, 2020, 154: 104234. https://doi.org/10.1016/j.phrs.2019.04.018
  34. Yang X, Gandhi YA, Duignan DB, et al. Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure–pharmacokinetic relationships. The AAPS Journal, 2009, 11: 511-525. https://doi.org/10.1208/s12248-009-9124-1
  35. Neupert W, Brugger R, Euchenhofer C, et al. Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases. British Journal of Clinical Pharmacology, 1997, 122: 487-492. https://doi.org/10.1038/sj.bjp.0701415