The pharmacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i.p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had received carboplatin (200-500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24 +/- 11. The peritoneal clearance of carboplatin was 8 +/- 3 ml/min, which was 12 times less than the plasma clearance (93 +/- 32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34% +/- 14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet = Dose - amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.
Toxicity of cisplatin can be decreased by concomitant administration of sodium thiosulfate, which perhaps chemically inactivates this platinum compound. We studied the disappearance of cisplatin and carboplatin in aqueous solutions of thiosulfate at 37 degrees C by means of liquid chromatography. At initial concentrations that were similar to therapeutic concentrations in plasma, both drugs disappeared, with half-lives of 66 and 537 min for cisplatin and carboplatin, respectively. At higher thiosulfate concentrations, as found in urine, the respective half-lives were 3.7 and 33.8 min. These values suggest that direct chemical interaction in the plasma compartment has limited therapeutic consequences, whereas the anti-toxic effect of thiosulfate might be explained by the rapid inactivation of cisplatin in the kidneys. Reaction products of cisplatin and thiosulfate bound instantaneously and mainly reversibly to plasma proteins. Protein-bound cisplatin was not released by added thiosulfate--which may explain why thiosulfate, to be effective, must be given in advance of and during cisplatin administration.
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