Evidence that fodipir (DPDP) binds neurotoxic Pt(2+) with a high affinity: An electron paramagnetic resonance study

Oxaliplatin typically causes acute neuropathic problems, which may, in a dose-dependent manner, develop into a chronic form of chemotherapy-induced peripheral neuropathy (CIPN), which is associated with retention of Pt(2+) in the dorsal root ganglion. A clinical study by Coriat and co-workers suggests that co-treatment with mangafodipir [Manganese(II) DiPyridoxyl DiPhosphate; MnDPDP] cures ongoing CIPN. These authors anticipated that it is the manganese superoxide dismutase mimetic activity of MnDPDP that explains its curative activity. However, this is questionable from a pharmacokinetic perspective. Another, but until recently undisclosed possibility is that Pt(2+) outcompetes Mn(2+)/Ca(2+)/Zn(2+) for binding to DPDP or its dephosphorylated metabolite PLED (diPyridoxyL EthylDiamine) and transforms toxic Pt(2+) into a non-toxic complex, which can be readily excreted from the body. We have used electron paramagnetic resonance guided competition experiments between MnDPDP ((10)logK(ML) ≈ 15) and K(2)PtCl(4), and between MnDPDP and ZnCl(2) ((10)logK(ML) ≈ 19), respectively, in order to obtain an estimate the (10)logK(ML) of PtDPDP. Optical absorption spectroscopy revealed a unique absorption line at 255 nm for PtDPDP. The experimental data suggest that PtDPDP has a higher formation constant than that of ZnDPDP, i.e., higher than 19. The present results suggest that DPDP/PLED has a high enough affinity for Pt(2+) acting as an efficacious drug in chronic Pt(2+)-associated CIPN.