Mechanisms of reaction of L-methionine with carboplatin and oxaliplatin in different media: a comparison with cisplatin

• Published in: Biopharmaceutics & drug disposition 1999-03, Vol.20 (2), p.107-116
• Main Authors: Heudi, Olivier, Mercier-Jobard, Sophie, Cailleux, Annie, Allain, Pierre
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemistry; Biological and medical sciences; Buffers; carboplatin; Carboplatin - chemistry; Chromatography, High Pressure Liquid; cisplatin; Cisplatin - chemistry; Drug Stability; General aspects; HPLC-UV; L-methionine; LC-MS; Mass Spectrometry; Medical sciences; Methionine - chemistry; Organoplatinum Compounds - chemistry; oxaliplatin; Pharmacology. Drug treatments; Phosphates; Spectrophotometry, Ultraviolet; Water
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/(SICI)1099-081X(199903)20:2<107::AID-BDD161>3.0.CO;2-0

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 [(NH3)2(met)]Pt, M4 and M5 [(met)2]Pt were characterized. Reaction of carboplatin with l‐met occurred via the formation of M0 [(NH3)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.