METABOLIC STUDIES OF AN ORALLY-ACTIVE PLATINUM ANTICANCER DRUG BY LIQUID-CHROMATOGRAPHY ELECTROSPRAY-IONIZATION MASS-SPECTROMETRY

Bis(acetato)amminedichloro(cyclohexylamine) platinum(IV) (JM216) is a new orally administered platinum complex with antitumor properties, an d is currently undergoing phase II clinical trials. When JM216 was inc ubated with human plasma ultrafiltrate, 93% of the platinum species we re protein-bound and 7% were unbound. The unbound platinum complexes i n the ultrafiltrates of human plasma were analysed using a liquid chro matography-electrospray ionization-mass spectrometry (LC-ESI-MS) metho d. Apart from the parent drug, four metabolites were identified and ch aracterised. These include JM118 [amminedichloro(cyclohexylamine) plat inum(II)], JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinu m(IV)] and the two isomers JM559 and JM518 [bis(acetato)amminechloro(c yclohexylamine) hydroxo platinum(IV)]. Their elemental compositions we re determined by accurate mass measurement during the LC analysis, to confirm their identities. Quantitation of these metabolites by off-lin e LC atomic absorption spectroscopy demonstrated that JM118 is the maj or metabolite in plasma from patients receiving JM216 treatment.