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Mechanisms of reaction of L ‐methionine with carboplatin and oxaliplatin in different media: a comparison with cisplatin
Author(s) -
Heudi Olivier,
MercierJobard Sophie,
Cailleux Annie,
Allain Pierre
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199903)20:2<107::aid-bdd161>3.0.co;2-0
Subject(s) - carboplatin , oxaliplatin , cisplatin , chemistry , adduct , platinum , medicinal chemistry , chemotherapy , biochemistry , catalysis , cancer , medicine , organic chemistry , colorectal cancer
The activity of platinum compounds is dependent on nucleophile substitution reactions. In this paper, we study the reactivity of L ‐met with carboplatin, oxaliplatin and cisplatin by following with HPLC‐UV the concentration of L ‐met and by characterizing the resulting adducts with LC‐MS. In the absence of NaCl, in water, the initial rate at which L ‐met concentration decreases with cisplatin, oxaliplatin and carboplatin is 0.25±0.007, 0.057±0.01 and 0.17±0.02 mM h −1 , respectively. In phosphate buffer this rate is 0.056±0.009 for cisplatin, 0.019±0.001 and 0.13±0.02 for carboplatin and oxaliplatin, respectively. Reactions of L ‐met with cisplatin occurred via its conversion into monoaqua species in water and into phosphato‐derivatives (AP) in phosphate buffer but finally the same methionine–platinum adducts M2 [(NH 3 ) 2 (met)]Pt, M4 and M5 [(met) 2 ]Pt were characterized. Reaction of carboplatin with l ‐met occurred via the formation of M0 [(NH 3 ) 2 (met)(CBDCA)]Pt whose structure is consistent with the direct interaction of L ‐met with carboplatin. However, the same final products as those found with cisplatin were characterized. The reaction of oxaliplatin with L ‐met proceeded through a mechanism similar to that of carboplatin to give M7 [(met)(DACH)]Pt. In the presence of NaCl, cisplatin directly reacted with L ‐met to yield at least five methionine–platinum adducts. The reaction of carboplatin gave the same adducts suggesting its transformation into cisplatin. The reaction of oxaliplatin with L ‐met occurred via the formation of aquated species A [(OH)(Cl)(DACH)]Pt which readily underwent reaction with L ‐met to form M6 [(met)(Cl)(DACH)]Pt and M7. This study shows that the reactivity of cisplatin, carboplatin and oxaliplatin is dependent on the media in which they occur. The discrepancy between their reactions with L ‐met could partly explain their therapeutic differences. Copyright © 1999 John Wiley & Sons, Ltd.