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, and is currently undergoing phase II clinical trials. When JM216 was incubated with human plasma ultrafiltrate, 93% of the platinum species were protein-bound and 7% were unbound. The unbound platinum complexes in the ultrafiltrates of human plasma were analysed using a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Apart from the parent drug, four metabolites were identified and characterised. These include JM118 [amminedichloro(cyclohexylamine) platinum(II)], JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinum(IV)] and the two isomers JM559 and JM518 [bis(acetato)amminechloro(cyclohexylamine) hydroxo platinum(IV)]. Their elemental compositions were determined by accurate mass measurement during the LC analysis, to confirm their identities. Quantitation of these metabolites by off-line LC atomic absorption spectroscopy demonstrated that JM118 is the major metabolite in plasma from patients receiving JM216 treatment.
Poon
G K
GK
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Raynaud
F I
FI
Mistry
P
P
Odell
D E
DE
Kelland
L R
LR
Harrap
K R
KR
Barnard
C F
CF
Murrer
B A
BA
D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D007477:Ions; D013058:Mass Spectrometry / Q000379:methods; D009944:Organoplatinum Compounds / Q000097:blood* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D014462:Ultrafiltration
D000970:Antineoplastic Agents; D007477:Ions; D009944:Organoplatinum Compounds; C097758:amminedichloro(cyclohexylamine)platinum(II); C081294:satraplatin