Biotransformation of the antineoplastic drug oxaliplatin : importance for effects and side effects
Author: Jerremalm, Elin
Date: 2008-04-25
Location: 10.00
Time: 10.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
View/ Open:
Thesis (653.8Kb)
Abstract
Oxaliplatin is a platinum-based cytostatic drug. It is used in
combination with 5-fluorouracil 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 cisplatin-induced apoptosis was dependent on calcium and superoxide, oxaliplatin-induced apoptosis was not.
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 cisplatin-induced apoptosis was dependent on calcium and superoxide, oxaliplatin-induced apoptosis was not.
List of papers:
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(10): 2116-21.
Pubmed
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(2): 436-8.
Pubmed
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(5): 891-4.
Pubmed
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(4): 278-83. Epub 2006 Apr 18
Pubmed
V. Broomand A, Jerremalm E, Yachnin J, Ehrsson H, Elinder F (2008). Oxaliplatin neurotoxicity no general ion channel surface-charge effect. [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." (Submitted)
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(10): 2116-21.
Pubmed
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(2): 436-8.
Pubmed
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(5): 891-4.
Pubmed
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(4): 278-83. Epub 2006 Apr 18
Pubmed
V. Broomand A, Jerremalm E, Yachnin J, Ehrsson H, Elinder F (2008). Oxaliplatin neurotoxicity no general ion channel surface-charge effect. [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." (Submitted)
Issue date: 2008-04-04
Rights:
Publication year: 2008
ISBN: 978-91-7357-570-6
Statistics
Total Visits
Views | |
---|---|
Biotransformation ...(legacy) | 826 |
Biotransformation ... | 129 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Biotransformation ... | 0 | 0 | 0 | 1 | 15 | 0 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 774 |
thesis.pdf | 275 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 329 |
China | 70 |
Germany | 66 |
Sweden | 54 |
South Korea | 37 |
Finland | 15 |
United Kingdom | 11 |
New Zealand | 10 |
Australia | 8 |
Denmark | 8 |
Top cities views
Views | |
---|---|
Beijing | 35 |
Sunnyvale | 26 |
Kiez | 25 |
Romeo | 21 |
Seoul | 16 |
Daegu | 15 |
Nürnberg | 11 |
Helsinki | 9 |
London | 8 |
Ashburn | 7 |