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Isolation of 10 cyclosporine metabolites from human bile

Wang, CP and Hartman, NR and Venkataramanan, R and Jardine, I and Lin, FT and Knapp, JE and Starzl, TE and Burckart, GJ (1989) Isolation of 10 cyclosporine metabolites from human bile. Drug Metabolism and Disposition, 17 (3). 292 - 296. ISSN 0090-9556

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Abstract

Ten metabolites of cyclosporine were isolated from the ethyl ether extract of bile from four liver transplant patients receiving cyclosporine. Two of the metabolites were unique and previously unidentified. Liquid-liquid partitioning into diethyl ether with subsequent defatting with n-hexane was used for the initial extraction form bile. Separation of the individual metabolites (A-J) was performed using a Sephadex LH-20 column and a gradient high performance liquid chromatographic method. The molecular weights of the isolated metabolites were determined by fast atom bombardment/mass spectrometry. Gas chromatography with mass spectrometic amino acid analysis was also used to identify the amino acid composition and the hydroxylation position of metabolites A, B, C, D, and G. Proton nuclear magnetic resonance spectra were utilized to disinguish the chemical shifts of N-CH 3 singlets and NH doublets of metabolites A, B, C, and D. Metabolites A, E, F, H, I, and J were reported previously in human urine and animal bile. Metabolites C and D are dihydroxylated compounds which cannot be clearly described as previously isolated compounds. Metabolites B and G are novel metabolites with a mass fragment which corresponded to a loss of 131 Da from the protonated molecular ion (MH + ) in the fast atom bombardment/mass spectrometry, suggesting that the double bond in amino acid 1 has been modified. Metabolites B and G were primarily isolated from the bile of one of the liver transplant patients which contained abnormally high concentrations of these two metabolites. The method described is an efficient procedure for isolating milligram quantities of the major metabolites with greater than 95% purity.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wang, CP
Hartman, NR
Venkataramanan, Rrv@pitt.eduRV
Jardine, I
Lin, FT
Knapp, JE
Starzl, TEtes11@pitt.eduTES11
Burckart, GJ
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 1989
Date Type: Publication
Journal or Publication Title: Drug Metabolism and Disposition
Volume: 17
Number: 3
Page Range: 292 - 296
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0090-9556
Other ID: uls-drl:31735062110709, Starzl CV No. 1028
Date Deposited: 08 Apr 2010 17:17
Last Modified: 13 Oct 2017 20:56
URI: http://d-scholarship.pitt.edu/id/eprint/4414

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