Carboplatin hydrolysis

Without added acid or nucleophile the lability of the starting compound is very low (<1 x 10"8 s"1) most probably because of the efficient ring-closing process [18]. The second step depends linearly on the pH with a rate constant of 1.61 x 10"4 M 1 s 1. In the presence of added Cl-, the final product of the hydrolysis is m-DDP although the relevance of similar process in vivo was questioned [18]. It has been reported that carboplatin bound to DNA retains the dicarboxylate group, probably as a monodentate ligand [19]. 

Reactions of [Pt(dipic)Cl] , dipic = dipicolinate, with 1-methylimida-zole or with 1,2-diaminoethane, monitored in DMF solution, involve replacement of chloride followed by opening of the dipic chelate ring (216). Kinetic data for acid-catalyzed ring opening in hydrolysis of [Pt(dipic)Cl] and of [Pt(glygly)Cl] (217) are compared with those for carboplatin (218) in Table VIII. 

Furthermore, RAPTA-C derivatives in which the chlorides have been replaced by chelating dicarboxylate ligands that resist hydrolysis display very similar in vitro activity to RAPTA-C [23]. Interestingly, RAPTA-C and carboplatin induce similar effects on DNA and yet their in vivo activities are markedly different [24]. This disparity may be attributed to targets other than DNA being relevant to provide their therapeutic effect. 

Other drug substances susceptible to hydrolysis include chloramphenicol, 13 chlorambucil,120 121 spirohydantoin mustard,122 alkyl halides such as clindamycin,123 azathio-prine,124 sulfides such as thimerosal,125-126 and platinum compounds such as carboplatin,127 as shown in Scheme 26. 

The hydrolysis of metallodrugs is often the key step in their activation, but the timescale is extremely variable, ranging from tenths of a second for titanocene dichloride, to hours for cisplatin, to days for carboplatin. We found on SPE that the interaction of cisplatin with DNA increases with the solution ageing time, especially at low concentrations of chlorides [50]. Each complex was therefore preactivated for 60 minutes before testing interaction with DNA, in order to permit the transformation into the active aqua species, for the complexes needing this incubation time, and to compare the behavior at the same solntion ageing time, for the complexes with a different rate of hydrolysis. 

Cisplatin and carboplatin are most commonly administrated to patients by intravenous injection. In human blood and in extracellular body fluids the physiological chloride concentration amounts to some 100 mM, and this is high enough to suppress hydrolysis, so that cisplatin can reach the outer surface of cells - perhaps recognized by receptor species in some cases - mainly as a neutral molecule. Carboplatin is even more hydrolytically stable. Early studies have shown that some 50% of the cisplatin may leave the body through the... 

The free chloride concentration inside cells is much lower (some 4 mM) and under these conditions hydrolysis of cisplatin can take place, albeit slowly. In fact the most important hydrolysis product is the [PtCl(H20)(NH3)2] cation which has a pK value of 6.5, and so above pH = 6 it starts to ionize to form [PtCl(OH)(NH3)2] The cationic Pt species with a labile aqua ligand is much more reactive than cisplatin, so the monoaqua species is most likely to react with DNA and other molecules in the cell. Carboplatin hydrolyses much slower, and far less is known in this case. Studies of this type for oxaliplatin, are also still lacking. Transport of platinum compounds through the nuclear membrane is also hardly studied. Whether a special nuclear localizing signal peptides (NLS) may play a role remains uncertain... 

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