In vitro immunosuppressive activity of tacrolimus dihydrodiol precursors obtained by chemical oxidation and identification of a new metabolite of SDZ-RAD by electrospray and electrospray-linked scan mass spectrometry

• Published in: Journal of mass spectrometry. Vol. 36; no. 8; pp. 889 - 901
• Main Authors: Lhoëst, G., Hertsens, R., Verbeeck, R. K., Maton, N., Wallemacq, P., Dehoux, J. P., Latinne, D.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2001; Wiley
• Subjects: Animals; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Biotransformation; Cells, Cultured; Chemistry; Chemistry, Analytical; Chromatography, High Pressure Liquid - methods; drug metabolism; Everolimus; Humans; Immunomodulators; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; immunosuppressive drugs; Lactones - chemistry; Life Sciences & Biomedicine; Lymphocyte Culture Test, Mixed; Lymphocytes - drug effects; Lymphocytes - immunology; mass spectrometry; Medical sciences; Microsomes, Liver - metabolism; Models, Molecular; Molecular Conformation; NADP - metabolism; Oxidation-Reduction; Pharmacology. Drug treatments; Physical Sciences; Science & Technology; SDZ-RAD; Sirolimus - analogs & derivatives; Sirolimus - chemistry; Sirolimus - pharmacokinetics; Sirolimus - pharmacology; Spectrometry, Mass, Electrospray Ionization - methods; Spectroscopy; Stereoisomerism; Swine; tacrolimus; Tacrolimus - chemistry; Tacrolimus - pharmacokinetics; Tacrolimus - pharmacology; Technology; RAPAMYCIN; PIG-LIVER MICROSOMES; tacrolimus; MACROLIDE; SDZ-RAD; immunosuppressive drugs; FK506; TRANSPLANTATION; EPOXIDE METABOLITE; BIOTRANSFORMATION; STREPTOMYCES; drug metabolism; mass spectrometry; FK-506; NEPHROTOXICITY; Sirolimus; Metabolite; Liver; HPLC chromatography; Fragmentation pattern; In vitro; Macrolide; Biological activity; Electrospray; Pig; Vertebrata; Mammalia; Tacrolimus; Analog; Animal; Epoxide; Oxidation; Artiodactyla; Immunosuppressive agent; Mass spectrometry; Ungulata
• ISSN: 1076-5174; 1096-9888
• DOI: 10.1002/jms.190

Different tacrolimus epoxides and dihydrodiol epoxides arising from the chemical oxidation of the parent drug are described. Open‐chain tautomeric forms involving the lactone function were identified for the tacrolimus epoxides. Moreover, the identification by electrospray and electrospray linked scan mass spectrometry of an SDZ‐RAD C16–C27 O‐demethyl 17, 18–19, 20–21, 22 tris‐epoxide new metabolite isolated from pig liver microsomes is reported. The in vitro immunosuppressive activity, using mixed lymphocyte reactions of the two macrolide reported oxidation compounds are discussed. Copyright © 2001 John Wiley & Sons, Ltd.