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Rapid biotransformation of satraplatin by human red blood cells in vitro
Jocelyn L Carr1, Malcolm D Tingle, Mark J McKeage
1Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. j.carr@auckland.ac.nz
Purpose:
Satraplatin is an orally administered platinum complex that has demonstrated clinical activity and manageable toxicity in phase II trials. The presence of several different platinum-containing species and very little intact parent drug in the systemic circulation indicates extensive biotransformation of satraplatin in vivo. To investigate the basis for the biotransformation of satraplatin, studies were carried out into the stability of the drug in whole blood and various other biological fluids in vitro.
Methods:
Concentrations of satraplatin and platinum-containing biotransformation products in incubation fluids were measured using high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). The fate of satraplatin-derived platinum in whole blood in vitro was determined by analysis of blood fractions for platinum by ICPMS.
Results:
In fresh human whole blood in vitro, satraplatin concentrations fell very rapidly, resulting in a half-life for the disappearance of the drug of only 6.3 min (95% CI, 5.9 to 6.7 min). After the addition of drug to red blood cells that had been prepared from whole blood and suspended in 0.9% NaCl, satraplatin also disappeared very rapidly. Satraplatin was much more stable in fresh human plasma (t(1/2) 5.3 h) and fully supplemented cell culture medium (t(1/2) 22 h). Two new platinum-containing species appeared on HPLC-ICPMS platinum chromatograms of methanol extracts of plasma after the addition of the drug to whole blood. Their identities were assigned as the platinum(II) complex known as JM118 and a platinated protein with similar electrophoretic mobility to that of serum albumin. During the incubation of satraplatin in blood, platinum associated with red blood cells at an accumulation half-life of 9.5 min (95% CI, 7.1 to 14.2 min). At equilibrium, 62% of the added platinum was associated with red blood cells in a form that was not exchangeable in methanol or 0.9% NaCl.
Conclusions:
The rapid disappearance of satraplatin from human blood in vitro depends upon the presence of red blood cells. Generation of JM118 and irreversibly bound membrane- and protein-associated platinum indicates that satraplatin undergoes rapid biotransformation in whole blood.