Comparative hydrolysis and plasma protein binding of cis-platin and carboplatin in human plasma in vitro.
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.
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada. jgailer@ucalgary.ca.
Melani
M
Sooriyaarachchi
Aru
A
Narendran
Jürgen
J
Gailer
D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry; D001711:Biotransformation; D016190:Carboplatin / Q000097:blood* / Q000737:chemistry; D002850:Chromatography, Gel; D002945:Cisplatin / Q000097:blood* / Q000737:chemistry; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D012709:Serum Albumin / Q000378:metabolism*; D013054:Spectrophotometry, Atomic; D014168:Transferrin / Q000378:metabolism*
D000970:Antineoplastic Agents; D012709:Serum Albumin; D014168:Transferrin; D016190:Carboplatin; D002945:Cisplatin