Pharmacokinetics of Oxaliplatin in Humans

Ehrsson, Hans; Wallin, Inger; Yachnin, Jeffrey

doi:10.1385/mo:19:4:261

Cited by 94 publications

(73 citation statements)

References 9 publications

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“…The rate of degradation varied among the patients (5-10%) as established by the in vitro studies, most probably due to differing amounts of red blood cells in the perfusate (cf. [9]). The mean elimination half-life in the perfusate and the percent dose absorbed were in general agreement with previous results [6,7], which is to be expected since the major Pt-containing agent in the perfusate is intact oxaliplatin.…”

Section: Discussionmentioning

confidence: 99%

“…A method for quantitative determination of the free fraction of intact oxaliplatin in blood ultrafiltrate has been developed [8] and applied to pharmacokinetic studies in humans [9][10][11]. The results establish that oxaliplatin has a drastically shorter terminal elimination half-life than was suggested based on results obtained by AAS, 15 min vs. 32-47 h respectively [12].…”

Section: Introductionmentioning

confidence: 95%

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Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion

Mahteme

Wallin

Glimelius

et al. 2008

Eur J Clin Pharmacol

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Objective To evaluate the perfusate and systemic kinetics of oxaliplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) using a selective analytical technique. Methods HIPEC was carried out in eight patients by the open abdomen coliseum technique for 30 min at 41.5-43°C with an average of 427 mg/m 2 of oxaliplatin in 5% dextrose solution. Blood and perfusate samples were collected during the perfusion. Additional blood samples were taken up to 2 h after the end of perfusion. The analysis was performed by liquid chromatography and post-column derivatization with N,N-diethyldithiocarbamate using microwave heating. Results The mean elimination half-life of oxaliplatin in the perfusate was 29.5 min (range 21.1-41.2 min) and in the peripheral circulation 24.7 min (range 21.7-27.7 min). The ratio of the areas under the time concentration curve in perfusate and blood was 12.8±2.9. ConclusionThe systemic exposure of oxaliplatin measured after HIPEC using a selective analytical technique is considerably lower than previously reported results obtained by atomic absorption spectroscopy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion

Mahteme

Wallin

Glimelius

et al. 2008

Eur J Clin Pharmacol

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“…Trifluorothymidine has a t 1/2 of about 15 min, but administration of several doses of TPI together with divided dosing of TFT increases the AUC and t 1/2 dramatically, which in turn could increase OHP-induced cytotoxicity when given simultaneously within the same time period. OHP is given by infusion and has a t 1/2 of less than 30 min (Ehrsson et al, 2002). This will result in a variable ratio, and therefore the variable ratio used in our experiments will better reflect a clinical situation.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

et al. 2007

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Oxaliplatin (OHP) is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA) adducts resulting in DNA-strand breaks and is used for the treatment of colorectal cancer. The pyrimidine analog trifluorothymidine (TFT) forms together with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. In this in vitro study the combined cytotoxic effects of OHP with TFT were investigated in human colorectal cancer cells as a model for TAS-102 combinations. In a panel of five colon cancer cell lines (WiDr, H630, Colo320, SNU-C4 and SW1116) we evaluated the OHP-TFT drug combinations using the multiple drug -effect analysis with CalcuSyn software, in which the combination index (CI) indicates synergism (CIo0.9), additivity (CI ¼ 0.9 -1.1) or antagonism (CI41.1). Drug target analysis was used for WiDr, H630 and SW1116 to investigate whether there was an increase in Pt-DNA adduct formation, DNA damage induction, cell cycle delay and apoptosis. Trifluorothymidine combined with OHP resulted in synergism for all cell lines (all CIo0.9). This was irrespective of schedule in which either one of the drugs was kept at a constant concentration (using variable drug ratio) or when the two drugs were added in a 1 : 1 IC 50 -based molar ratio. Synergism could be increased for WiDr using sequential drug treatment schedules. Trifluorothymidine increased Pt-DNA adduct formation significantly in H630 and SW1116 (14.4 and 99.1%, respectively; Po0.05). Platinum-DNA adducts were retained best in SW1116 in the presence of TFT. More DNA-strand breaks were induced in SW1116 and the combination increased DNA damage induction (420%) compared with OHP alone. Exposure to the drugs induced a clear cell-cycle S-phase arrest, but was dose schedule and cell line dependent. Trifluorothymidine (TFT) and OHP both induced apoptosis, which increased significantly for WiDr and SW1116 after TFT -OHP exposure (18.8 and 20.6% respectively; Po0.05). The basal protein levels of ERCC1 DNA repair enzyme were not related to the DNA damage that was induced in the cell lines. In conclusion, the combination of TFT with the DNA synthesis inhibitor OHP induces synergism in colorectal cancer cells, but is dependent on the dose and treatment schedule used.

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“…One paper reported the pharmacokinetics of oxaliplatin itself rather than of platinum after oxaliplatin infusion 38 . The half-life (t 1/2 ) of oxaliplatin is 14.1 minutes.…”

Section: Generalitiesmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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Pharmacokinetics of Oxaliplatin in Humans

Cited by 94 publications

References 9 publications

Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion

Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

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