Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: application to clinical pharmacokinetic studies with oxaliplatin

ELOXATIN(R) (Oxaliplatin) is a novel platinum containing anti-cancer agent with a diaminocyclohexane carrier ligand which has been approved in several major European countries. Clinical studies have demonstrated that the comp ound exhibits marked activity against colorectal cancers in combination wit h 5-fluorouracil (5-FU). The aim of this work was to develop and Validate a highly sensitive inductively coupled plasma mass spectrometry assay for th e determination of oxaliplatin-derived platinum in plasma ultrafiltrate, pl asma and whole blood and to apply this technique to clinical pharmacokineti c studies with oxaliplatin. Ultratrace detection of platinum in plasma ultr afiltrate was achieved using ultrasonic nebulisation combined with ICP-M. T his technique allows detection of platinum at the 0.001 mug Pt/ml level in only 100 mul of matrix. Assays in blood and plasma utilised a standard Mein hardt nebuliser and spray chamber, achieving detection limits of 0.1 mug Pt /ml in 100 and 200 mul of matrix, respectively. The assays were validated ( accuracy and precision within +/- 15%) over the concentration ranges: 0.001 -0.250 mug Pt/ml in plasma ultrafiltrate and 0.1-10 mug Pt/ml for plasma an d whole blood. The effect of sample digestion, dilution, long term frozen s torage and quantitation in the presence of 5-FU were also investigated and validated. The method was used to monitor platinum exposure following oxali platin administration (130 mg/m(2)) to cancer patients. Following a 2 h i.v . infusion, peak platinum levels declined in a triphasic manner in all bloo d compartments. Free platinum was detected in plasma ultrafiltrate at low l evels (0.001-0.010 mug Pt/ml) for up to 3 weeks. In conclusion, a highly se nsitive and specific assay has been developed for the determination of plat inum in biofluids. This method enabled characterisation of the long term ex posure to platinum in patients following oxaliplatin treatment. (C) 2000 El sevier Science B.V. All rights reserved.