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.

Coordination compounds in cancer: Past, present and perspectives

“…Due to low chemical stability of cisplatin, the direct intravenous administration is preferred over the other forms. In the blood stream, cisplatin rapidly interacts with plasma proteins such as human serum albumin (HSA), haemoglobin (Hb) or transferrin (Tf) (Rudnev et al, 2005) and 24 h after administration, 95% of cisplatin is bound to plasma proteins (Sooriyaarachchi et al, 2011). Cisplatin is widely distributed into body fluids and tissues, reaching the highest concentrations in kidneys (0.4-2.9 mg/g), liver (0.5-3.7 mg/g wet weight), and prostate (1.6-3.6 mg/g).…”

Preparation, Characterization, and Antitumor Activities of Miriplatin-Loaded Liposomes

“…1,2 Despite being one of the most effective classes of chemotherapeutics, platinum drugs (cisplatin, carboplatin, and oxaliplatin) do have several significant drawbacks: severe side effects 3 (such as neurotoxic, myelotoxicity), short blood circulation times, 4 and the universal drug resistance. 5 Because of these limitations, there has been strong interest in the development of novel platinum-based therapeutics to not only lower toxicity but also improve therapeutic efficacy.…”

The anticancer drug cisplatin can cross-link the interdomain zinc site on human albumin

“…One day after intravenous administration, 65 to 98% of cisplatin is bound to blood plasma 20 proteins, 6 and most of the Pt (50-61%) from cisplatin added to human blood plasma at physiologically -relevant doses is bound to albumin. 7 Albumin, a 66 kDa single-chain protein consisting of 3 isostructural domains, 8 and present in blood at ca. 0.6 mM , can bind and transport a variety of endogenic and exogenic 25 substances, such as fatty acids, bilirubin, pharmaceuticals and metal ions.…”