Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach

Motawi, Tarek K.; Abdelgawad, Hanan Muhammad; Shahin, Nancy N.

doi:10.1016/j.fct.2013.02.042

Cited by 7 publications

(2 citation statements)

References 89 publications

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“…There are many reports in the literature describing the pharmacokinetic parameters of drugs that are altered in states of protein‐energy malnutrition but, surprisingly, very few focus on anticancer drugs . Erlotinib was selected to evaluate the role of malnutrition on the absorption kinetics when absorption interactions take place given that lung cancer patients suffer severe undernourishment, antineoplastic drugs have a narrow therapeutic index and the pharmacokinetic profile of erlotinib was previously described to be altered in undernourishment .…”

Section: Discussionmentioning

confidence: 99%

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

Pérez-Pitarch

Guglieri-López

Nácher

et al. 2017

Biopharm & Drug Disp

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The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright © 2017 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

Pérez-Pitarch

Guglieri-López

Nácher

et al. 2017

Biopharm & Drug Disp

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“…However, the therapeutic application of cisplatin is limited by tumor drug resistance and systemic toxicity. At high doses, cisplatin toxicity increases (39,40); whereas low doses of cisplatin are not effective for the treatment of prostate cancer. Therefore, a comprehensive therapy that improves the current status of cancer chemotherapy is required.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin in combination with programmed cell death protein 5 increases antitumor activity in prostate cancer cells by promoting apoptosis

Zhu

Yang

Gao

2015

Molecular Medicine Reports

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Prostate cancer is the most common type of cancer affecting males. The aim of the present study was to investigate the antitumor effect of cisplatin in combination with programmed cell death protein 5 (Pdcd5) on Du145 prostate cancer cells and to elucidate the underlying mechanisms of action. An MTT cell viability assay was performed in order to determine the proliferation rate of Du145 cells. The results demonstrated that Du145 cells treated with cisplatin for 48 h had an IC50 value>200 µM; however, following transfection of Pdcd5 in combination with treatment with various concentrations of cisplatin, the proliferation rates of Du145 and PC3 prostate cancer cells were significantly decreased in a dose‑dependent manner, with IC50 values of 114.1 and 50.6 µM, respectively. Annexin V‑fluorescein isothiocyanate/propidium iodide dual labeling analyses demonstrated a significant increase in the apoptotic rate of Du145 cells following transfection of Pcdc5 in combination with cisplatin treatment. Furthermore, western blot analysis revealed a marked increase in activated caspase‑3 expression in Du145 cells as well as a decreased ratio of Bcl‑2/Bax. In conclusion, the results of the present study demonstrated that Pdcd5 increased the chemosensitivity of prostate cancer cells and decreased the toxicity of cisplatin via activation of the receptor‑associated apoptotic pathway; this may therefore indicate the combined use of cisplatin and Pdcd5 as a novel therapeutic strategy for the treatment of prostate cancer.

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Impact of nutritional status on the pharmacokinetics of erlotinib in rats

Pérez-Pitarch

Nácher

Merino

et al. 2015

Biopharm & Drug Disp

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Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.

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Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach

Cited by 7 publications

References 89 publications

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats

Cisplatin in combination with programmed cell death protein 5 increases antitumor activity in prostate cancer cells by promoting apoptosis

Impact of nutritional status on the pharmacokinetics of erlotinib in rats

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