[Pharmacokinetic properties of platinium derivatives]

Abstract

The three platinum derivatives currently available share many pharmacokinetic and pharmacodynamic (PK-PD) properties but present also some distinct characteristics, due to their structural differences. They result in different systemic PK-PD and metabolic behaviour and toxicity profile. Oxaliplatin is quickly transformed into dach-platinum, the active metabolite, by loosing oxalate chain. Eighty to eighty-eight per cent of platinum are bound to proteins, as for cisplatin, whereas carboplatin is less reactive. Cisplatin and oxaliplatin active metabolites, i.e. monoaquo platin and dach-platin quickly react with small proteins with sulfhydryl groups, such as glutathione, cysteine and methionine, and then with high molecular weight proteins, such as albumin and gammaglobulins through covalent link. Thus, their terminal half lives are long, about ten days, but no platinum accumulation has been reported in plasma with oxaliplatin, whereas after cisplatin administration, both total and ultrafiltrable platinum progressively accumulate in plasma. This difference may play a role in the lack of oxaliplatin nephrotoxicity and its more delayed and reversible neurotoxicity. On the other hand, carboplatin is more stable, less bound to proteins and is largely excreted inchanged in urine. This can explain that it passes more easily through the blood brain barrier. Erythrocytes represent an important deep compartment, especially for oxaliplatin, a little bit less for cisplatin. Oxaliplatin is trapped in erythrocytes through a covalent binding to globin. There, its half life is identical to that of erythrocytes. According to certain authors, this trapping would be involved in the incidence of anemia. On the contrary, carboplatin is quickly extruded from erythrocytes. The three derivatives kinetics in plasma present a wide interindividual variability, resulting in differences in term of toxicity and efficacy. For the three of them, plasma clearance is correlated to creatinine clearance, but only carboplatin dosage can be individually adjusted, based on creatinine clearance measurement, thanks to its simple renal excretion, due to exclusive glomerular filtration, and after Calvert's, Egorin's and Chatelut's population kinetics studies. Cisplatin renal excretion is more complex, combining reabsorption and secretion processes. Therefore, individual dosage adjustment needs platinum concentration measurement in plasma, but there is no general agreement on the platinum species to measure, ultrafiltrable or bound. Oxaliplatin is too recent in clinical practice and still lacks of PK-PD data. These characteristics can help us for a better knowledge of the three platinum derivatives clinical properties, both in term of kinetics, behaviour and toxicity.