title: Kinetics of acid-catalyzed degradation of cyclosporin A and its analogs in aqueous solution.
abstract: The kinetics and mechanism of the degradation of cyclosporin A have been studied under aqueous acidic conditions. The rate of degradation was found to be specific acid-catalyzed over the pH range studied (1-4), with isocyclosporin A as the predominant degradation product. Selective reduction of the olefinic bond of the amino acid 2-N-methyl-(R)-((E)-2-butenyl)-4-methyl-L-threonine (MeBmt) did not affect the overall degradation kinetics and product distribution of cyclosporin A. These observations indicate that the alternative degradation pathway involving intramolecular alkoxy addition to the olefinic bond of amino acid MeBmt apparently does not significantly contribute to the overall degradation kinetics of cyclosporin A in the pH range 1-4. The chemical reactivity of O-acetyl-cyclosporin A was examined to probe the governing mechanism for the isomerization of cyclosporin A. Under identical conditions, O-acetyl-cyclosporin A showed a much greater chemical stability than cyclosporin A, consistent with a mechanism involving the hydroxyoxazolidine intermediate. The chemical stability of cyclosporin C, which contains two beta-hydroxyl groups, was also examined. The rate and product distribution for the degradation of cyclosporin C suggest that under aqueous acidic conditions it undergoes N,O-acyl migration solely at the amino acid residue MeBmt. Additionally, the impact of side-chain bulkiness of amino acid MeBmt was examined by studying the degradation kinetics of a series of cyclosporin A analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence.
authors.forename: R
authors.initials: R
authors.lastname: Oliyai
authors.forename: M
authors.initials: M
authors.lastname: Safadi
authors.forename: P G
authors.initials: PG
authors.lastname: Meier
authors.forename: M K
authors.initials: MK
authors.lastname: Hu
authors.forename: D H
authors.initials: DH
authors.lastname: Rich
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000595:Amino Acid Sequence; D016572:Cyclosporine / Q000737:chemistry*; D003524:Cyclosporins / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007536:Isomerism; D007700:Kinetics; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012996:Solutions; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D003524:Cyclosporins; D012996:Solutions; D014867:Water; D016572:Cyclosporine