The impact of whole human blood on the kinetic inertness of platinum() prodrugs - an HPLC-ICP-MS study

The potential advantage of platinum( iv ) complexes as alternatives to classical platinum( ii )-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow has been developed...

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Bibliographic Details
Published in:	Dalton transactions : an international journal of inorganic chemistry 2018-04, Vol.47 (15), p.5252-5258
Main Authors:	Theiner, Sarah, Grabarics, Márkó, Galvez, Luis, Varbanov, Hristo P, Sommerfeld, Nadine S, Galanski, Mathea S, Keppler, Bernhard K, Koellensperger, Gunda
Format:	Article
Language:	eng
Subjects:	Biotransformation Carboplatin - blood Carboplatin - pharmacokinetics Chemical compounds Chemistry Chromatography, High Pressure Liquid Coordination Complexes - blood Coordination Complexes - pharmacokinetics Drugs Erythrocytes Human behavior Humans Hydrophobic and Hydrophilic Interactions Inductively coupled plasma mass spectrometry Kinetics Ligands Lipophilicity Mass spectrometry Metabolites Nanospheres - chemistry Organoplatinum Compounds - blood Organoplatinum Compounds - pharmacokinetics Oxaliplatin Oxidation-Reduction Pharmacology Platinum Prodrugs - pharmacokinetics Workflow
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Summary:	The potential advantage of platinum( iv ) complexes as alternatives to classical platinum( ii )-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow has been developed to investigate the reductive biotransformation and kinetic inertness of platinum( iv ) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of platinum( iv ) complexes in blood pellets and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. An analytical approach based on reversed-phase (RP)-ICP-MS was used to monitor the parent compound and the formation of metabolites using two different extraction procedures. The ligand coordination sphere of the platinum( iv ) complexes had a significant impact on their accumulation in red blood cells and on their degree of kinetic inertness in whole human blood. The most lipophilic platinum( iv ) compound featuring equatorial chlorido ligands showed a pronounced penetration into blood cells and a rapid reductive biotransformation. In contrast, the more hydrophilic platinum( iv ) complexes with a carboplatin- and oxaliplatin-core exerted kinetic inertness on a pharmacologically relevant time scale with notable amounts of the compound accumulated in the plasma fraction. The reductive biotransformation of platinum( iv ) prodrugs was investigated in whole human blood by HPLC-ICP-MS.
ISSN:	1477-9226 1477-9234