Determination of the platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) in human urine by liquid chromatography–tandem mass spectrometry

Abstract

A validated stable isotope dilution liquid chromatography–tandem mass spectrometry assay for the novel platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) (ZD0473) in human urine has been developed. This method uses selected reaction monitoring on the transition of m/ z 393 [M+NH 4] + to m/ z 304 [M+NH 4−NH 3−2×H 35Cl] + for ZD0473, and m/ z 400 [M+NH 4] + to m/ z 310 [M+NH 4−NH 3−H 35Cl− 2H 35Cl] + for the internal standard [ 2H 7]ZD0473. Standard curves were prepared over the range from 0.15 to 50 μg/ml. The lower limit of quantitation was 0.2 μg/ml for 100 μl of urine. This simple, rapid, reliable, and sensitive method of quantitation displayed acceptable accuracy and precision over the 3 days of assay validation. A novel platinum adduct was formed during the storage of ZD0473 in human urine. The adduct did not correspond to any of the typical sulfhydryl adducts that have been identified previously for platinum drugs. Formation of the adduct was prevented by the addition of 50% (w/v) sodium chloride to the urine. The assay can be used to quantify intact ZD0473 in the urine of subjects dosed with this new platinum drug.