Comparative protein binding, stability and degradation of satraplatin, JM118 and cisplatin in human plasma in vitro.
1. Satraplatin is an investigational orally administered platinum-based antitumour drug. The present study compared the plasma protein binding, stability and degradation of satraplatin with that of its active metabolite JM118 and cisplatin. 2. The platinum complexes were incubated in human plasma for up to 2 h at 37 degrees C and quantified in plasma fractions by inductively coupled plasma-mass spectrometry on- or off-line to high-performance liquid chromatography. 3. All three platinum drugs became irreversibly bound to plasma proteins and showed negligible reversible protein binding. They were also unstable in plasma and generated one or more platinum-containing degradation products during their incubation. However, the three platinum complexes differed in the kinetics of their instability and protein binding, as well as in the number of degradation products formed during their incubation. 4. In conclusion, the plasma protein binding, instability and degradation of satraplatin and its active metabolite JM118 are qualitatively similar to that of cisplatin and other clinically approved platinum-based drugs. Quantitative differences in their irreversible protein binding and degradation were related to their respective physiochemical properties and bioactivation mechanisms.
Bell
Deanna N
DN
Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Liu
Johnson J
JJ
Tingle
Malcolm D
MD
Rattel
Benno
B
Meyer
Thorsten Ulf
TU
McKeage
Mark J
MJ
D000970:Antineoplastic Agents / Q000097:blood* / Q000378:metabolism; D002945:Cisplatin / Q000097:blood* / Q000378:metabolism; D004355:Drug Stability; D015507:Drugs, Investigational / Q000378:metabolism*; D006801:Humans; D009944:Organoplatinum Compounds / Q000097:blood* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D009944:Organoplatinum Compounds; C097758:amminedichloro(cyclohexylamine)platinum(II); C081294:satraplatin; D002945:Cisplatin