Oxaliplatin reacts with DMSO only in the presence of water

Abstract

Herein we show that oxaliplatin reacts rapidly with DMSO in aqueous solutions, despite being stable in pure DMSO and pure water. Furthermore, the reactivity of the clinically applied Pt(ii) drugs in water/DMSO and PBS/DMSO mixtures, and the nature of the species formed were investigated by MS, NMR and RP-HPLC techniques.

Scheme 1. Formation of Pt-DMSO adducts in DMSO/H₂O and DMSO/PBS (pH = 7.4) solutions of oxaliplatin.

Fig. 1. Relative intensity of the peaks corresponding to intact oxaliplatin ([Pt(DACH)(Ox) + (H/Na/K)]⁺, red ), [Pt(DACH)(OH)(DMSO)]⁺ (black ■) and [Pt(DACH)(Ox)(DMSO) + (H/Na/K)]⁺ (blue ) as a function of time in the ESI MS from a solution of oxaliplatin in DMSO after dilution with water (1 : 20). See Table 1 for details of peak assignments.

Fig. 2. (a) Change in the relative intensity of the MS peaks corresponding to intact oxaliplatin as a function of time in a clinical formulation of oxaliplatin (12.6 mM in 5% glucose solution), diluted with different water/DMSO and PBS/DMSO mixtures as determined by ESI MS. (b) Time-dependent change in the relative intensity of peaks corresponding to the species formed in a clinical formulation of oxaliplatin after dilution with water/DMSO (10 : 1) as observed in the ESI MS+ spectra.

Fig. 3. ¹³C NMR spectra of oxaliplatin analogue with ¹³C₂-labeled oxalate in a D₂O/DMSO-d₆ (10 : 1) mixture as a function of time at RT (a, chelating oxalate ligand; b, monodentate oxalate; c, uncoordinated oxalate).

Fig. 4. Rate of reaction of the oxaliplatin analogue featuring ¹³C₂-labeled oxalate and DMSO in different water/DMSO mixtures determined by ¹³C NMR spectroscopy.