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

J Ma,J Verweij,Jhm Schellens,Hj Kolker,G Stoter,He Van Ingen

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.

Highlights

CDDP binds almost irreversibly to plasma and cellular components (Yotsuyanagi et al, 1991)
Roswell Park Memorial Institute (RPMI) 1640 medium was obtained from Brunschwig (Amsterdam, The Netherlands), bovine calf serum (BCS) from Hyclone (Logan, UT, USA), dimethylsulphoxide (DMSO) and platin (Pt) standard solution (500 p.p.m.) from Baker (Deventer, The Netherlands), phosphate-buffered saline (PBS) from Boom (Meppel, The Netherlands) and insulin Neerlandicum from Organon (Oss, The Netherlands)
The cell line was maintained in a continuous logarithmic culture in RPMI-1640 medium with HEPES and phenol red supplemented with 10% BCS, 10 mM sodium bicarbonate, 2 mM glutamine, penicillin 111 IU ml', streptomycin 103 g ml1', gentamycin

Summary

Introduction

CDDP binds almost irreversibly to plasma and cellular components (Yotsuyanagi et al, 1991). This results in an extremely long retention of CDDP in tissues (Loehrer & Einhorn, 1984). The cytotoxic activity of CDDP is very likely correlated to the covalent binding to DNA, so-called inter- and intrastrand adduct formation (Plooy et al, 1984). This is not an irreversible process because of the cellular capacity to remove the formed adducts (DNA repair) (Plooy et al, 1984; Fichtinger-Schepman et al, 1987)

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Discussion

Conclusion