Determination of biotransformation products of platinum drugs in rat and human urine

Abstract

Cisplatin is an extremely effective cancer chemotherapeutic agent, but its use is often accompanied by toxicity. Second generation drugs such as carboplatin are becoming more widely used because of reduced toxicity. Since biotransformation products have been implicated in the toxic responses, we have begun to investigate the reactions of cisplatin and carboplatin with potential biological ligands. Reaction products were characterized using HPLC with inductively coupled plasma mass spectrometry (HPLC-ICP-MS), 1H and 13C NMR and fast atom bombardment mass spectrometry (FAB-MS). Three Pt-creatinine complexes, cis-[Pt(NH3)2Cl(Creat)](*), cis[Pt(NH3)2(H2O)(Creat)]2+ and cis-Pt(NH3)2(Creat)2]2+, were synthesized and the platinum was shown to coordinate to the ring nitrogen, N(3). Human urine samples from patients on cisplatin chemotherapy were shown to contain cisplatin, its hydrolysis product and biotransformation products containing Pt-creatinine, Pt-urea and Pt-uric acid complexes. Urine from carboplatin patients shows fewer biotransformation products. Studies with control and diabetic (protected against cisplatin toxicity) rats showed systematic differences in the biotransformation products formed on administration of cisplatin.