Biotransformation of the Antineoplastic Drug Oxaliplatin: Importance for Effects and Side Effects

Oxaliplatin is a platinum-based cytostatic drug. It is used in combination with 5fluorouracil and leucovorin for palliative and adjuvant treatment of metastatic colorectal cancer. The biotransformation of oxaliplatin is non-enzymatic and complexes with water, chloride, glutathione and methionine have been reported to be present in plasma ultrafiltrate from patients. Oxaliplatin gives rise to DNA adducts and, consequently, DNA damage. This is the predominant explanation for its antineoplastic effect. It is not known to what extent the parent drug and/or its biotransformation products contribute to the cytotoxic effect. Common side effects of oxaliplatin treatment are nausea, vomiting and neurotoxicity. To create a more solid ground for the understanding of the effects of oxaliplatin, we have elucidated the chemistry of the compound. Oxaliplatin contains a diaminocyclohexane and an oxalato ligand. In study I, hydrolysis of oxaliplatin was found to occur in two consecutive steps. In the first step, the oxalato ring was opened and in the second step it was lost, replaced by two water molecules. The ring-opening was reversible and the closing step was much faster than the opening step. In study II, the acid dissociation constant of the oxalato monodentate intermediate was determined to 7.23. At physiological pH less than 1 % of oxaliplatin will be present in the shape of the ring-opened intermediate. The reaction of oxaliplatin with chloride was investigated in study III. The oxalato ring was opened, replaced by one chloride and then it was lost, replaced by another chloride. The initial reaction was fast with a half-life of 5-10 minutes. The cytotoxicity of the ring-opened species, [Pt(dach)oxCl], was studied in vitro and was found not to exceed that of oxaliplatin. In study IV, the degradation of oxaliplatin in plasma ultrafiltrate was in good agreement with the degradation of oxaliplatin in the presence of a mixture of chloride, cysteine, methionine and glutathione at physiological concentrations. It has been proposed that the acute neurotoxic side effects of oxaliplatin treatment involve voltage-gated ion channels. Since charged molecules can affect ion channel function, we hypothesized in study V that [Pt(dach)oxCl] could be involved. We studied the effects of oxaliplatin and [Pt(dach)oxCl] on voltage-gated potassium channels, but concluded that we did not see any effects in our Xenopus oocyte experimental system. Apoptosis is commonly induced by DNA-damaging drugs. Apoptotic pathways induced by oxaliplatin and cisplatin were compared in study VI. While cisplatininduced apoptosis was dependent on calcium and superoxide, oxaliplatin-induced apoptosis was not. LIST OF PUBLICATIONS I. Jerremalm E, Videhult P, Alvelius G, Griffiths WJ, Bergman T, Eksborg S, Ehrsson H (2002) Alkaline hydrolysis of oxaliplatin − isolation and identification of the oxalato monodentate intermediate. J Pharm Sci 91: 21162121. II. Jerremalm E, Eksborg S, Ehrsson H (2003) Hydrolysis of oxaliplatin − evaluation of the acid dissociation constant for the oxalato monodentate complex. J Pharm Sci 92: 436-438. III. Jerremalm E, Hedeland M, Wallin I, Bondesson U, Ehrsson H (2004) Oxaliplatin degradation in the presence of chloride: identification and cytotoxicity of the monochloro monooxalato complex. Pharm Res 21: 891894. IV. Jerremalm E, Wallin I, Yachnin J, Ehrsson H (2006) Oxaliplatin degradation in the presence of important biological sulphur-containing compounds and plasma ultrafiltrate. Eur J Pharm Sci, 28: 278-83. V. Broomand A, Jerremalm E, Yachnin J, Ehrsson H, Elinder F (2008) Oxaliplatin neurotoxicity – no general ion channel surface-charge effect. Manuscript submitted. VI. Hellberg V, Wallin I, Eriksson S, Hernlund E, Jerremalm E, Berndtsson M, Arnér ESJ, Shoshan M, Ehrsson H, Laurell G (2008) Toxicity of cisplatin and oxaliplatin – the importance of cochlear kinetics for ototoxicity. Manuscript submitted. The previously published material was reprinted with kind permission from John Wiley & Sons, Inc (I and II), Springer Science and Business Media (III) and Elsevier (IV). CONTENTS