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Stereoselective binding properties of naproxen glucuronide diastereomers to proteins

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Abstract

The stability of naproxen glucuronide (NAP-G) diastereomers was investigated in buffer, 0.3% and 3% human serum albumin (HSA) solutions, and human plasma.R-NAP-G was found to be less stable in phosphate buffer than itsS-diastereomer, whereas incubation media containing protein in general increased the degradation rate of NAP-G but also caused a change of the stereoselective stability where theR-NAP-G was more stable thanS-NAP-G. Reversible binding of NAP-Gs to HSA (0.3%) was investigated and compared with the corresponding properties of naproxen (NAP) enantiomers. NAP-G diastereomers exibited a considerable and stereoselective affinity to HSA, although less than that observed for the NAP enantiomers.In vitro irreversible binding of NAP-Gs to HSA, human and rat plasma proteins was also investigated. Irreversible binding was higher forR-NAP-G (50 μM) than forS-NAP-G (50 μM) in all incubation media. This stereoselective difference was observed with HSA containing medium as well as in rat and human plasma. Incubation with unconjugated NAP did not lead to irreversible binding. Preincubation of HSA with acetylsalicylic acid (≈ 11 mM) and glucuronic acid (50 mM) decreased the extent of irreversible binding suggesting involvement of lysine residues for covalent binding. Preincubation withS-NAP also decreased the irreversible binding yield.

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References

  1. T. B. Vree, M. V. D. Biggelaar-Martea, C. P. W. G. M. Verwey-Van Wissen, J. B. Vree, and P. J. M. Guelen. Pharmacokinetics of naproxen, its metabolite desmethylnaproxen, and their acyl glucuronides in humans.Biopharm. Drug Dispos. 14:491–502 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. M. Salmon, C. Fenselau, J. O. Cukier, and G. B. Odell. Rapid transesterification of bilirubin glucuronides in methanol.Life Sci. 15:2069–2078 (1975).

    Article  Google Scholar 

  3. R. B. van Breemen and C. Fenselau. Reaction of 1-O-acyl glucuronides with 4-(p-nitrobenzyl) pyridine.Drug Metab. Dispos. 14:197–201 (1986).

    PubMed  Google Scholar 

  4. H. Spahn-Langguth and L. Z. Benet. Acyl glucuronides revisited: Is the glucuronidation process a toxification as well as a detoxification mechanism?Drug Metab. Rev. 24:5–48 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. A. Ding, J. C. Ojingwa, A. F. McDonagh, A. L. Burlingame, and L. Z. Benet. Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry.Proc. Natl. Acad. Sci. U.S. 90:3797–3801 (1993).

    Article  CAS  Google Scholar 

  6. A. Ding, P. Zia-Amirhosseini, A. F. McDonagh, A. L. Burlingame, and L. Z. Benet. Reactivity of tolmetin glucuronide with human serum albumin: Identification of binding sites and mechanisms of reaction by tandem mass spectrometry.Drug Metab. Dispos. 23:369–376 (1995).

    CAS  PubMed  Google Scholar 

  7. S. Iwakawa, H. Spahn, L. Z. Benet, and E. T. Lin. Stereoselective binding of the glucuronide conjugates of carprofen enantiomers to human serum albumin.Biochem. Pharmacol. 39:949–953 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. D. S. Wells, F. W. Janssen, and H. W. Ruelius. Interactions between oxaprozin glucuronide and human serum albumin.Xenobiotica 17:1437–1449 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. J. C. Ojingwa, H. Spahn-Langguth and L. Z. Benet. Reversible binding of tolmetin, zomepirac, and their glucuronide conjugates to human serum albumin and plasma.J. Pharmacokin. Biopharm. 22:19–40 (1994).

    Article  CAS  Google Scholar 

  10. H. Spahn. Formation of diastereomeric derivatives of 2-arylpropionic acids using L-leucinamide.J. Chromatog. 423:339 (1987).

    Article  Google Scholar 

  11. B. Buszewski, M. E. Moueli, K. Albert, and E. Bayer. Influence of the structure of chemically bonded C18 phases on HPLC separation of naproxen glucuronide diastereomers.J. Liq. Chromatog. 13:505–524 (1990).

    Article  CAS  Google Scholar 

  12. C. Volland, H. Sun, J. Dammeyer, and L. Z. Benet. Stereoselective degradation of the fenoprofen acyl glucuronide enantiomers and irreversible binding to plasma protein.Drug Metab. Dispos. 19:1080–1086 (1991).

    CAS  PubMed  Google Scholar 

  13. M. Iwaki, A. Bischer, A. C. Nguyen, A. F. McDonagh, and L. Z. Benet. Stereoselective disposition of naproxen glucuronide in the rat.Drug Metab. Dispos. 23:1099–1103 (1995).

    CAS  PubMed  Google Scholar 

  14. M. V. Calvo and A. Dominguez-Gil. Binding of naproxen to human albumin. Interaction with palmitic acid.Int. J. Pharm. 16:215–223 (1983).

    Article  CAS  Google Scholar 

  15. A. Mortensen, E. Bjørn Jensen, P. Bernth Petersen, S. Husted, and F. Andreasen. The determination of naproxen by spectrofluorometry and its binding to serum proteins.Acta Pharmacol. Toxicol. 44:277–283 (1979).

    Article  CAS  Google Scholar 

  16. L. R. Pohl and R. V. Branchflower. Covalent binding of electrophilic metabolites to macromolecules.Meth. Enzymol. 77:43–50 (1981).

    Article  CAS  PubMed  Google Scholar 

  17. P. Zia-Amirhosseini, H. Spahn, and L. Z. Benet. Measurement of naproxen, desmethylnaproxen, and their conjugates in plasma and urine.Pharm. Res. 5:S-13 (1988).

    Google Scholar 

  18. D. E. Drayer. Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: An overview.Clin. Pharmacol. Ther. 40:125–133 (1986).

    Article  CAS  PubMed  Google Scholar 

  19. R. Runkel, D. Rochielli, H. Sevelius, M. Chaplin, and E. Segre. Nonlinear plasma level response to high doses of naproxen.Clin. Pharmacol. Ther. 15:261–266 (1974).

    CAS  PubMed  Google Scholar 

  20. A. Bischer, M. Iwaki, P. Zia-Amirhosseini, and L. Z. Benet. Stereoselective reversible binding properties of the glucuronide conjugates of fenoprofen enantiomers to human serum albumin.Drug Metab. Dispos. 23:900–903 (1995).

    CAS  PubMed  Google Scholar 

  21. H. Spahn, S. Iwakawa, E. T. Lin, and L. Z. Benet. Procedures to characterizein vivo andin vitro enantioselective glucuronidation properly: studies with benoxaprofen glucuronides.Pharm. Res. 6:125–132 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. H. Spahn, S. Iwakawa, and L. Z. Benet. Stereoselective formation and degradation of flunoxaprofen glucuronides in microsomal incubations.Pharm. Res. 5:S-200 (1988).

    Article  Google Scholar 

  23. J. E. Walker. Lysine residue 199 of human serum albumin is modified by acetylsalicylic acid.FEBS Lett. 66:173–175 (1976).

    Article  CAS  PubMed  Google Scholar 

  24. H. W. Ruelius, S. K. Kirkman, E. M. Young, and F. W. Janssen. Reaction of oxaprozin-1-O-acyl glucuronide in solutions of human plama and albumin.Adv. Exp. Med. Biol. 197:431–441 (1986).

    Article  CAS  PubMed  Google Scholar 

  25. J. C. Ojingwa, H. Spahn-Langguth, and L. Z. Benet. Reversible binding of tolmetin, zomepirac, and their glucuronide conjugates to human serum albumin and plasma.J. Pharmacokin. Biopharm. 22:19–40 (1994).

    Article  CAS  Google Scholar 

  26. P. C. Smith and C. O. Wang. Nonenzymic glycation of albumin by acyl glucuronidesin vitro—Comparison of reactions with reducing sugars.Biochem. Pharmacol. 44:1661–1668 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. L. Z. Benet, H. Spahn-Langguth, S. Iwakawa, C. Volland, T. Mizuma, S. Mayer, E. Mutschler, and E. T. Lin. Predictability of the covalent binding of acidic drugs in man.Life Sci. 53:PL141–146 (1993).

    Article  CAS  PubMed  Google Scholar 

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This paper is dedicated to Professor Richard Neidlein, Pharmaceutical Chemistry Institute, Heidelberg, in commemoration of his 65th birthday. Supported in part by National Institutes of Health Grants GM 36633 and DK 26307.

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Bischer, A., Zia-Amirhosseini, P., Iwaki, M. et al. Stereoselective binding properties of naproxen glucuronide diastereomers to proteins. Journal of Pharmacokinetics and Biopharmaceutics 23, 379–395 (1995). https://doi.org/10.1007/BF02353639

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