Isolation, identification and immunosuppressive activity of SDZ-IMM-125 metabolites from human liver microsomes
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Summary
SDZ-IMM-125 N-methyl leucine 9 hydroxylated in the γ position is a metabolite which was extracted from incubated human liver microsomes and subsequently separated by normal and reverse-phase HPLC. This metabolite was identified by fast atom bombardment mass spectrometry, electrospray-ms/ms mass spectrometry and nuclear magnetic resonance spectroscopy. Thein vitro 50% inhibitory concentration, tested against bidirectional mixed lymphocyte reaction was 80 μg/l indicating that this metabolite does not retainin vitro immunosuppressive activity most probably due to the structural modification of SDZ-IMM-125 in the recognized binding region to cyclophilin A reducing its binding affinity relative to the parent drug.
Keywords
SDZ-IMM-125 human liver microsomes metabolism mass spectrometry nuclear magnetic resonance spectroscopyPreview
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References
- 1.Schreier M.H., Zenke G., Borel J.F., Baumann G. (1992): The continuing search for new immunomodulators. Transplant. Proc., 24 (Suppl 2): 19–21.PubMedGoogle Scholar
- 2.Mason J. (1989): Pharmacology of cyclosporine (Sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals. Pharmacol. Rev., 42: 423–434.Google Scholar
- 3.Walkinshaw M.D., Kallen J., Weber H.P., Widmer A., Zurini M. (1992): Immunophilin structure: a template for immunosuppressive drug design? Transplant. Proc., 24 (Suppl 2): 8–13.PubMedGoogle Scholar
- 4.Hiestand P.C., Gräber M., Hurtenbach U.et al. (1992): The new cyclosporin derivative, SDZ IMM 125:in vitro andin vivo pharmacological effects. Transplant. Proc., 24 (Suppl 2): 31–38.PubMedGoogle Scholar
- 5.Bruelisauer A., Kawai R., Misslin P., Lemaire M. (1994): Absorption and disposition of SDZ IMM 125, a new cyclosporine derivative, in rats after single and repeated administration. Drug Metab. Dispos., 22: 194–199.PubMedGoogle Scholar
- 6.Wagner O., Schreier E., Heitz F., Maurer G. (1987): Tissue distribution, disposition, and metabolism of cyclosporine in rats. Drug Metab. Dispos., 15: 377–383.PubMedGoogle Scholar
- 7.Dieden R., Verbeeck R.K., Maton N., Latinne D., Lhoëst G.J.J. (1997): Identification andin vitro immunosuppressive activity of a SDZ-IMM-125 metabolite isolated from phenobarbital-induced rabbit liver microsomes. Xenobiotica, 27: 933–949.PubMedCrossRefGoogle Scholar
- 8.Amar-Costesec A., Beaufay H., Wibo M.et al. (1974): Analytical study of microsomes and isolated subcellular membranes from rat liver. J. Biol. Chem., 261: 201–212.Google Scholar
- 9.Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.I. (1951): Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193: 265–275.PubMedGoogle Scholar
- 10.Omura T., Sato R. (1964): The carbon monoxide-binding pigment of liver microsomes. 1. Evidence for its hemoprotein nature. J. Biol. Chem., 239: 2370–2378.PubMedGoogle Scholar
- 11.Derome A., Williamson M. (1990): Rapid-pulsing artifacts in double-quantum-filtered COSY. J. Magn. Reson., 88: 177–185.Google Scholar
- 12.Bax A., Davis D.G. (1985): MLEV-17 based 2D homonuclear magnetization transfer spectroscopy. J. Magn. Reson., 65: 355–360.Google Scholar
- 13.Vickers A.E.M., Fischer V., Connors S.et al. (1992): Cyclosporin A metabolism in human liver, kidney, and intestine slices: comparison to rat and dog slices and human cell lines. Drug Metab. Dispos., 20: 802–809.PubMedGoogle Scholar
- 14.Pflügi G., Kallen J., Schirmer T., Jansonius J.N., Zurini M.G.M., Walkinshaw M.D. (1993): X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature, 361: 91–94.CrossRefGoogle Scholar
- 15.Braun W., Kallen J., Mikol V., Walkinshaw M.D., Wüthrich K. (1995): Three-dimensional structure and actions of immunosuppressants and their immunophilins. FASEB J., 9: 63–72.PubMedGoogle Scholar
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