Abstract
This study evaluated the impact of calcium and magnesium on the in vitro degradation and in vivo clearance of oxaliplatin. Intact oxaliplatin and Pt(DACH)Cl2 were measured in incubation solutions by HPLC-UV. A clinical study determined changes in plasma concentrations of calcium and magnesium in cancer patients and their impact on oxaliplatin clearance. Kinetic analyses modelled oxaliplatin degradation reactions in vitro and contributions to oxaliplatin clearance in vivo. Calcium and magnesium accelerated oxaliplatin degradation to Pt(DACH)Cl2 in chloride-containing solutions in vitro. Kinetic models based on calcium and magnesium binding to a monochloro-monooxalato ring-opened anionic oxaliplatin intermediate fitted the in vitro degradation time-course data. In cancer patients, calcium and magnesium plasma concentrations varied and were increased by giving calcium gluconate and magnesium sulfate infusions, but did not alter or correlate with oxaliplatin clearance. The intrinsic in vitro clearance of oxaliplatin attributed to chloride-, calcium- and magnesium-mediated degradation predicted contributions of <2.5% to the total in vivo clearance of oxaliplatin. In conclusion, calcium and magnesium accelerate the in vitro degradation of oxaliplatin by binding to a monochloro-monooxalato ring-opened anionic intermediate. Kinetic analysis of in vitro oxaliplatin stability data can be used for in vitro prediction of potential effects on oxaliplatin clearance in vivo.
Highlights
Calcium and magnesium have been implicated in the mechanism and clinical prevention of oxaliplatin-induced neurotoxicity
This study showed that calcium and magnesium accelerate oxaliplatin degradation by binding to the monochloro-monooxalato ring-opened anionic oxaliplatin intermediate, [Pt(DACH)oxCl]−, that forms in chloride-containing physiological solutions in vitro
We showed that the in vitro degradation of oxaliplatin to Pt(DACH)Cl2 was faster in the presence of calcium and magnesium by directly quantifying both intact oxaliplatin and Pt(DACH)Cl2 using HPLC-UV
Summary
Calcium and magnesium have been implicated in the mechanism and clinical prevention of oxaliplatin-induced neurotoxicity. Abnormal spontaneous high-frequency motor unit action potentials are detectable on electromyography, reflecting hyper-excitability of these peripheral nerves[10,11,12] The mechanism of this acute neurotoxicity of oxaliplatin has been proposed to be related to the prolonged opening of calcium-dependent voltage-gated sodium channels resulting from chelation of calcium by oxalate[13,14,15,16]. A clinical study was undertaken to determine changes in plasma concentrations of calcium and magnesium in cancer patients given oxaliplatin with or without infusions of calcium gluconate and magnesium sulfate, and their impact on oxaliplatin clearance These in vitro and clinical datasets provided an opportunity to develop and exemplify experimental approaches for prediction of effects on oxaliplatin clearance in vivo from oxaliplatin stability data generated in vitro
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