Investigations on the metabolic pathways of cyclosporine: I. Excretion of cyclosporine and its metabolites in human bile--isolation of 12 new cyclosporine metabolites
| Autor: | K. Kohlhaw, Schottmann R, K F Sewing, J Greipel, Jörg S. Bleck, S. Strohmeyer, Uwe Christians, Hans-Martin Schiebel, R. Kownatzki |
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| Rok vydání: | 1991 |
| Předmět: |
Magnetic Resonance Spectroscopy
Spectrophotometry Infrared Health Toxicology and Mutagenesis Metabolite Glucuronates Toxicology Hydroxylation Biochemistry Aldehyde Mass Spectrometry chemistry.chemical_compound Biotransformation Pharmacokinetics Bile Humans Chromatography High Pressure Liquid Pharmacology chemistry.chemical_classification Aldehydes Chemistry General Medicine Metabolism Amino acid Metabolic pathway Dealkylation Cyclosporine |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 21(9) |
| ISSN: | 0049-8254 |
| Popis: | 1. Cyclosporine metabolites of known and unknown structures were isolated, by semi-preparative h.p.l.c., from human bile from the T-tube of liver-grafted patients, who received cyclosporine treatment. Their structures were elucidated by FAB mass spectrometry and 1H-n.m.r. spectroscopy. 2. Twelve of the cyclosporine metabolites, with known chemical structures, were isolated and identified using authentic standard material. 3. Four isolated fractions contained tri-hydroxylated metabolites; two fractions contained di-hydroxylated, demethylated metabolites; one fraction contained a tri-hydroxylated, demethylated metabolite; and one fraction a mono-hydroxylated, demethylated metabolite. The exact metabolism sites were partially defined. 4. Two carboxylated cyclosporine metabolites, of which one was hydroxylated in an unknown position, were isolated. 5. One new metabolite proved to be a glucuronylated phase II metabolite. Deglucuronylation of this metabolite by beta-glururonidase yielded metabolite AM1c. The proposed structure was AM1c-Glc; is a proposed extension of the Hawk's Cay nomenclature of the cyclosporine metabolites for glucuronylated metabolites. 6. One of the unknown metabolites was hydroxylated in two positions of amino acid 1. The proposed nomenclature was 'AM11d', where '1d' indicates hydroxylation at the delta C of amino acid 1. 7. A metabolite with an aldehyde functional group at amino acid 1, which had two isomeric forms, was isolated. I.r.-spectroscopy indicated that isomerism may be caused by conjugation of the aldehyde group with the double bond between C6 and C7 of amino acid 1. |
| Databáze: | OpenAIRE |
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