Issue 1, 2011

Comparative hydrolysis and plasma protein binding of cis-platin and carboplatin in human plasma in vitro

Abstract

Platinum-based anti-cancer drugs are widely used to treat cancer in patients, but they also exhibit severe toxic side-effects. Considering that cis-platin and carboplatin are intravenously administered, their biotransformations in the bloodstream are likely to be directly involved in determining their toxic side-effects, but they are poorly understood. We added pharmacologically relevant doses of cis-platin or carboplatin to human plasma from healthy male or female volunteers in vitro at 37 °C and determined the platinum-distribution in plasma after 5 min, 3 h and 24 h using size exclusion chromatography-inductively coupled plasma atomic emission spectrometry (SEC-ICP-AES). The results revealed a negligible inter-individual variation of the platinum-distribution between males and females and faster hydrolysis of cis-platin than carboplatin. Related to this, 95% of platinum was protein-bound 24 h after the addition of cis-platin to plasma, whereas 40% of platinum was protein-bound in the case of carboplatin. Interestingly, cis-platin and carboplatin-derived platinum species appeared to bind to the same 3 plasma proteins at the 3 h time point and thereafter. The analysis of cis-platin and carboplatin-spiked phosphate buffered saline (PBS) revealed a common platinum-containing hydrolysis product that was also detected in plasma. Since cis-platin is associated with more toxic side-effects in patients than carboplatin (even though it is administered at lower doses), our in vitro data suggest that the toxic side-effects of the investigated platinum-drugs may be predominantly determined by the indiscriminate translocation of the parent drugs to malignant and healthy cells. This information may help to mitigate the toxic side-effects of platinum-containing drugs by devising strategies to delay the influx of the parent drugs into non-target tissues.

Graphical abstract: Comparative hydrolysis and plasma protein binding of cis-platin and carboplatin in human plasma in vitro

Supplementary files

Article information

Article type
Paper
Submitted
27 Sep 2010
Accepted
10 Nov 2010
First published
06 Dec 2010

Metallomics, 2011,3, 49-55

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