title: [Binding of epirubicin to human plasma protein and erythrocytes: interaction with the cytoprotective amifostine].
abstract: The in vitro binding rate of epirubicin (EPR) to different plasma proteins, control serum, red blood cells and whole blood was investigated without and with the cytoprotective agent amifostine. The binding rate of EPR to plasma proteins fractions and red blood cells dependend on the concentration of the matrix components. EPR was bound more than 90% to human serum alpha-globulin (alpha-HSG), to human serum albumine (HSA) and human serum beta-globuline (beta-HSG) at 80 to 90%, in the case of human serum gamma-globulin (gamma-HSG) the binding rate amounted 75%. The binding rate of EPR to RBCs in whole blood samples reached 38%. Within the observed concentration range of proteins (1-40 micrograms/ml, depending on the protein concentration) AMI caused a reduction of the protein-bound amount of EPR in the range from 2 to 19% of HSA, 4 to 20 in the case of beta-HSG, 2 to 32% in the case of alpha-HSG and 17 to 21% for gamma-HSG. In the whole blood samples the binding of EPR to proteins dropped from 45 to 32% and RBC-partitioning from 38 to 32%. Two compounds with free thiol groups, cystein and glutathione, were compared with AMI in regard to lowering the binding rate of EPR to HSA: the effect was exactly in the same order of magnitude: -17% for AMI, -21.0% for cystein and -20.8% for glutahion (p < 0.002). For a negative control, cystin and phenylalanin were tested, too: both compounds showed no influence on the protein binding of EPR: 63.8% binding rate in the control group, 65.2% in the presence of cystin and 64.6% in the presence of phenylalanin (statistically not significant). The present results indicate, that binding of EPR to serum proteins is reduced in the presence of AMI by interaction of the thiol-group with the protein and that the thiophosphoric ester bond in the test solution must cleave rapidly.
authors.affiliation: Institut für Pharmazeutische Chemie, Universität Wien, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Pernkopf
authors.forename: G
authors.initials: G
authors.lastname: Tesch
authors.forename: K
authors.initials: K
authors.lastname: Dempe
authors.forename: H
authors.initials: H
authors.lastname: Kletzl
authors.forename: J
authors.initials: J
authors.lastname: Schüller
authors.forename: M
authors.initials: M
authors.lastname: Czejka
mesh_terms: D004999:Amifostine / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism; D003545:Cysteine / Q000097:blood; D004317:Doxorubicin / Q000097:blood; D015251:Epirubicin / Q000097:blood*; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D006801:Humans; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D001798:Blood Proteins; D015251:Epirubicin; D004317:Doxorubicin; D005978:Glutathione; D003545:Cysteine; D004999:Amifostine