New insights into the biotransformation and pharmacokinetics of oxaliplatin

Jerremalm, Elin; Wallin, Inger; Ehrsson, Hans

doi:10.1002/jps.21732

Cited by 45 publications

(35 citation statements)

References 49 publications

(68 reference statements)

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“…They reported that the fast initial degradation of oxaliplatin can be coupled to the fast formation of [Pt(dach)oxOH]-and the final product, the diaquo complex (Pt(dach)OH2). Oxaliplatin and [Pt(dach)oxOH]-rapidly reach an equilibrium state, especially in the presence of low chloride concentration, and the [Pt(dach)oxOH]-is slowly converted to (Pt (dach)OH2) (10,11). Therefore, we decided that the latter reaction was a rate-limiting step for oxaliplatin binding to biological substances.…”

Section: Resultsmentioning

confidence: 97%

Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives

et al. 2010

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Section: Resultsmentioning

confidence: 97%

Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives

et al. 2010

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“…The probability of IK Ca -channel openings in these cells can be decreased by TRAM-34 or clotrimazole and be subject to stimulation by DCEBIO. Additionally, It needs to be noted that the OXAL concentration used in our study tends to be greater than that achieved in the plasma of treated patients (3.6-5.6 µM) [35,36]. Any changes of IK Ca -channel activity suppressed by OXAL depend on not only the OXAL concentration, but also membrane potential, intracellular Ca 2+ concentration and cell volume.…”

Section: Discussionmentioning

confidence: 99%

“…Any changes of IK Ca -channel activity suppressed by OXAL depend on not only the OXAL concentration, but also membrane potential, intracellular Ca 2+ concentration and cell volume. Moreover, the OXAL concentrations may not be similar to those present in tissues, because there are areas outside the circulation where OXAL can accumulate at much higher concentrations [36]. For example, heated intraperitoneal chemotherapy was previously demonstrated to produce high peritoneal and tumor OXAL concentrations with limited systemic absorption [37].…”

Section: Discussionmentioning

confidence: 99%

“…For example, heated intraperitoneal chemotherapy was previously demonstrated to produce high peritoneal and tumor OXAL concentrations with limited systemic absorption [37]. One of the reasons could arise from the possibility that OXAL can react with endogenous sulfur compounds (e.g., glutathione) [36,37]. It has also been shown that in patients heavily pretreated with OXAL, a redistribution of the pool of intra-erythrocytic OXAL biotransformation products into the plasma may aggravate neurotoxic effect of OXAL [38].…”

Section: Discussionmentioning

confidence: 99%

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The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells

Huang

2015

Cell Physiol Biochem

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Oxaliplatin (OXAL) is a third-generation organoplatinum which is effective against advanced cancer cells including glioma cells. How this agent and other related compounds interacts with ion channels in glioma cells is poorly understood. OXAL (100 µM) suppressed the amplitude of whole-cell K⁺ currents (I_K); and, either DCEBIO or ionomycin significantly reversed OXAL-mediated inhibition of I_K in human 13-06-MG glioma cells. In OXAL-treated cells, TRAM-34 did not suppress I_K amplitude in these cells. The intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca) channels subject to activation by DCEBIO and to inhibition by TRAM-34 or clotrimazole were functionally expressed in these cells. Unlike cisplatin, OXAL decreased the probability of IK_Ca-channel openings in a concentration-dependent manner with an IC₅₀ value of 67 µM. No significant change in single-channel conductance of IK_Ca channels in the presence of OXAL was demonstrated. Neither large-conductance Ca²⁺-activated K⁺ channels nor inwardly rectifying K⁺ currents in these cells were affected in the presence of OXAL. OXAL also suppressed the proliferation and migration of 13-06-MG cells in a concentration- and time-dependent manner. OXAL reduced IK_Ca-channel activity in LoVo colorectal cancer cells. Taken together, the inhibition by OXAL of IK_Ca channels would conceivably be an important mechanism through which it acts on the functional activities of glioma cells occurring in vivo.

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“…Newer studies suggest that not only the platinum derivates but also the intact oxaliplatin may exert cytotoxic effects [ 25 ]. The cytotoxicity of oxaliplatin arises from DNA damage by several mechanisms as DNA adducts formation, inter-and intra-strand DNA cross-link and DNA protein cross-links [ 26 ].…”

Section: Oxaliplatinmentioning

confidence: 99%

Systemic Therapy for Patients with Colorectal Cancer: State of the Art

Pfeiffer

Qvortrup

Tabernero

2014

Multidisciplinary Treatment of Colorectal Cancer

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For more than 50 years, 5-fl uorouracil (FU) has been the cornerstone in the treatment of patients with CRC [ 2 ]. The antitumour activity arises from several mechanisms ( Fig. 13.1 ) including AbstractRecent modalities and strategies have increased the complexity of treatment choice in patients with colorectal cancer (CRC), and therefore all cases should be assessed at a multidisciplinary conference.Adjuvant chemotherapy for 6 months increases the chance of cure by absolutely 5 % in stage II and 10-15 % in stage III. Targeted therapy is not recommended in the adjuvant setting.Treatment options in patients with non-resectable CRC are based on the extent of disease (resectable/potential resectable/non-resectable) and symptoms. Surgery fi rst or chemotherapy fi rst in patients with synchronous metastasis is one of several yet unsolved questions which should be discussed at a MDT in each case taking into account patients symptoms and performance.

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New insights into the biotransformation and pharmacokinetics of oxaliplatin

Cited by 45 publications

References 49 publications

Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives

Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives

The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells

Systemic Therapy for Patients with Colorectal Cancer: State of the Art

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