title: In vitro stability, plasma protein binding and blood cell partitioning of 14C-carboplatin.
abstract: Radiochemically pure 14C-labeled carboplatin, cis-diammine [1,1-cyclobutane (1-14C) dicarboxylato (2-)-0,0'] platinum (II), was added to fresh human, dog and rat plasma, at concentrations ranging from 1 to 100 micrograms 14C-carboplatin/ml. After 10 min incubation at ambient temperature, the plasma was ultrafiltered in Amicon Centrifree micropartition units to generate protein-free plasma ultrafiltrate (PU). Total radioactivity was determined by liquid scintillation counting. A mean (+/- SD) of 102% +/- 2.0%, 99.5% +/- 1.9%, and 99.0% +/- 1.0% of the 14C-carboplatin added to fresh human, dog, and rat plasma respectively was recovered in the PU. 14C-carboplatin was incubated at 37 degrees C with fresh plasma (60 micrograms/ml) and urine (200 micrograms/ml) from humans and dogs for 120 h, and samples were removed at appropriate times for analysis of carboplatin, 1,1-cyclobutane dicarboxylic acid and cyclobutane carboxylic acid. The latter were separated by HPLC on a C-18 column with a mobile phase of H2O/CH3CN/0.3 M tetrabutylammonium phosphate (880:50:20 v/v/v), and the column eluants at the retention time of each compound were collected and counted for total radioactivity. Carboplatin degraded in each of the matrices with a corresponding release of 1,1-cyclobutane dicarboxylic acid. 14C-carboplatin (50 micrograms/ml) was incubated at 37 degrees C with fresh human, dog and rat blood and the distribution of radioactivity into the cellular fraction was determined. Radioactivity did not distribute into the blood cells of humans or dogs, but after 5 h, 44% of the radioactivity in rat blood was associated with the cellular fraction. These results show that carboplatin, at physiological concentrations, does not bind instantaneously and reversibly to the plasma proteins of rat, dog or human, and that the molecule slowly degrades in plasma and urine in vitro with the release of 1,1-cyclobutane dicarboxylic acid. The remaining diammine platinum (II) portion of the molecule therefore accounts for the essentially irreversible protein binding of the platinum from carboplatin.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Bristol-Myers Company, Syracuse, NY 13221.
authors.forename: R C
authors.initials: RC
authors.lastname: Gaver
authors.forename: A M
authors.initials: AM
authors.lastname: George
authors.forename: G
authors.initials: G
authors.lastname: Deeb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood*; D001773:Blood Cells / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D016190:Carboplatin; D002851:Chromatography, High Pressure Liquid; D003503:Cyclobutanes / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D009944:Organoplatinum Compounds / Q000097:blood*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D003503:Cyclobutanes; D009944:Organoplatinum Compounds; D016190:Carboplatin