title: Clinical pharmacokinetics of carboplatin.
abstract: The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high-performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein-bound platinum and metabolites, declined triexponentially; plasma half-lives (t1/2 lambda 1, 0.2 to 0.4 hr; t1/2 lambda 2, 1.3 to 1.7 hr; t1/2 lambda 3, 22 to 40 hr) and total body clearance (CLTB 2.8 +/- 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterable platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2 lambda 1, 0.50 hr; t1/2 lambda 2, 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (t1/2-26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half-life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first-generation analog cisplatin.
authors.affiliation: Bristol Myers Research Institute, Ltd., Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Oguri
authors.forename: T
authors.initials: T
authors.lastname: Sakakibara
authors.forename: H
authors.initials: H
authors.lastname: Mase
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
authors.forename: K
authors.initials: K
authors.lastname: Kimura
authors.forename: R D
authors.initials: RD
authors.lastname: Smyth
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D016190:Carboplatin; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000493:pharmacokinetics; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood / Q000652:urine; D011485:Protein Binding; D013054:Spectrophotometry, Atomic
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA; D016190:Carboplatin; D002945:Cisplatin