Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion.
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.
Ma
J
J
Department of Medical Oncology, Dr Daniel den Hoed Kliniek, Rotterdam, The Netherlands.
Verweij
J
J
Kolker
H J
HJ
van Ingen
H E
HE
Stoter
G
G
Schellens
J H
JH
D000230:Adenocarcinoma / Q000378:metabolism*; D002470:Cell Survival; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D004273:DNA, Neoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D004273:DNA, Neoplasm; C057270:cisplatin-DNA adduct; D004247:DNA; D002945:Cisplatin