Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion

Br J Cancer. 1994 May;69(5):858-62. doi: 10.1038/bjc.1994.166.

Abstract

The profiles of an i.v. bolus and 3 h and 20 h infusion of cisplatin (CDDP) were simulated in vitro by using a culture of the IGROV1 human ovarian cancer cell line. Disappearance of pharmacologically active unbound CDDP was accomplished by adding human albumin to the medium. Total and unbound CDDP and CDDP-DNA adduct levels were quantitated by atomic absorption spectroscopy (AAS), and tumour cell survival was measured by the clonogenic assay. The design of the experiment resulted in non-significant differences in the magnitude of the area under the concentration-time curve (AUC) of unbound CDDP between the three dose-input functions (AUC i.v. bolus, 6.34 +/- 0.36; 3 h infusion, 6.35 +/- 0.59; and 20 h infusion, 6.76 +/- 0.40 micrograms h ml-1). Also, the differences between the area under the CDDP-DNA adduct-time curves (AUA) of the three dose-input functions were not significant. The initial rate of decline of the CDDP-DNA adduct-time curve was significantly higher for the i.v. bolus and 3 h infusion than for the 20 h infusion. There was a log-linear relationship between the AUC of unbound CDDP and cell survival. These relationships were not significantly different between the three dose-input functions. Variation in the rate of input of CDDP leads to differences in the shape of the AUC and AUA without significant effects on cell survival.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Cell Survival
  • Cisplatin / administration & dosage
  • Cisplatin / metabolism
  • Cisplatin / pharmacokinetics*
  • DNA / metabolism
  • DNA Adducts*
  • DNA, Neoplasm / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Ovarian Neoplasms / metabolism*
  • Tumor Cells, Cultured

Substances

  • DNA Adducts
  • DNA, Neoplasm
  • cisplatin-DNA adduct
  • DNA
  • Cisplatin