Local Irradiation Modulates the Pharmacokinetics of Metabolites in 5-Fluorouracil—Radiotherapy–Pharmacokinetics Phenomenon

Liu, Ju Han; Tsai, Tung Hu; Chen, Yu-Jen; Wang, Li Ying; Liu, Hsin‐Yu; Hsieh, Ching‐Chuan

doi:10.3389/fphar.2020.00141

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…The Hsieh study found that radiation significantly reduced the exposure of 5-fluorouracil and its metabolites in vivo and altered their pharmacokinetic profiles. Compared to radiotherapy or chemotherapy alone, 5-fluorouracil combined with radiotherapy leads to serious hematological and gastrointestinal reactions ( Chen et al, 2017 ; Liu et al, 2020 ). The incidence of adverse reactions of sorafenib in combination with radiotherapy exceeds 30%, and there is evidence that the occurrence of toxic and side effects is closely related to the changes in the pharmacokinetics of sorafenib ( Hsieh et al, 2020 ; Tsai et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Radiotherapy changes the physiological state of the body and can even cause pathological changes, which affect the absorption, distribution, metabolism, and excretion of chemotherapeutic drugs in the body. This results in a change in the pharmacokinetic profile of drugs known as the “radiotherapy-pharmacokinetic” (“RT-PK”) phenomenon ( Chen et al, 2017 ; Ishiyama et al, 2019 ; Hsieh et al, 2020 ; Liu et al, 2020 ). Studies have also shown that many drugs can be affected by the RT-PK phenomenon and that radiotherapy significantly changes the pharmacokinetics of many chemotherapeutic drugs, such as 5-fluorouracil, cisplatin, sorafenib, and irinotecan.…”

Section: Introductionmentioning

confidence: 99%

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Effect of X-ray radiation on the pharmacokinetics of apatinib in vivo in rats

et al. 2022

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Purpose: The “radiotherapy-pharmacokinetic” (“RT-PK”) phenomenon refers to the fact that radiation can significantly alter the pharmacokinetic behavior of a drug. At present, it is not clear whether there is an “RT-PK” phenomenon that can affect apatinib during concurrent chemoradiotherapy. In this study, we used a rat irradiation model to study the effects of X-ray radiation on absorption, tissue distribution, and excretion of apatinib.Method: Healthy Sprague-Dawley (SD) rats were randomly divided into control and radiation groups. The radiation group was given an appropriate dose of abdominal X-ray radiation, while the control group was not given irradiation. After 24 h of recovery, both groups were given apatinib solution 45 mg/kg by gavage. A quantitative LC-MS/MS method was developed to determine the concentration of apatinib in the rats, so as to compare the differences between the control and radiation groups and thus investigate the modulating effect of radiation on the pharmacokinetics of apatinib in rats.Results: After abdominal X-ray irradiation, the area under the curve (AUC0-t) of apatinib in rat plasma decreased by 33.8% and 76.3% at 0.5 and 2 Gy, respectively. Clearance (CL) and volume of distribution (Vd) increased and were positively correlated with radiation dose. X-ray radiation significantly reduced the concentration of apatinib in the liver and small intestine, and there was no tissue accumulation. In excretion studies, we found that X-ray radiation reduced the cumulative excretion of apatinib in feces and urine by 11.24% and 86.17%, respectively.Conclusion: Abdominal X-ray radiation decreased plasma exposure, tissue distribution, and excretion of apatinib in rats, suggesting that the RT-PK phenomenon affects apatinib. We speculate that this RT-PK phenomenon is closely related to changes in metabolic enzymes in vivo. In clinical practice, when apatinib is combined with radiotherapy, attention should be paid to adjusting the dose of apatinib and optimizing the treatment plan to alleviate the adverse effects of this RT-PK phenomenon.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of X-ray radiation on the pharmacokinetics of apatinib in vivo in rats

et al. 2022

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“…Both off-target and treatment doses have similar interactions with chemotherapy drugs, such as 5-FU [ 47 , 48 ] and cisplatin [ 49 , 50 ], and multikinase inhibitors, such as sorafenib [ 8 ]. Similarly, the current study also confirmed that off-target and SBRT doses were comparable in their ability to modulate the PK of lenvatinib.…”

Section: Discussionmentioning

confidence: 99%

Impact of Local Liver Irradiation Concurrent Versus Sequential with Lenvatinib on Pharmacokinetics and Biodistribution

Tsai

Chen

Wang

et al. 2021

Cancers

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Concurrent and sequential regimens involving radiotherapy (RT) and lenvatinib were designed with off-target or stereotactic body radiation therapy (SBRT) doses in a freely moving rat model to evaluate the effect of RT on the pharmacokinetics (PK) of lenvatinib. Liver RT concurrent with lenvatinib decreased the area under the concentration–time curve of lenvatinib concentration (AUClenvatinib) by 51.1% with three fractions of 2 Gy (RT2Gy×3f’x, p = 0.03), and 48.9% with RT9Gy×3f’x (p = 0.03). The AUClenvatinib increased by 148.8% (p = 0.008) with RT2Gy×3f’x, and 68.9% (p = 0.009) with RT9Gy×3f’x in the sequential regimen compared to the concurrent regimen. There were no differences in the AUClenvatinib between RT2Gy×3f’x and RT9Gy×3f’x in the concurrent or sequential regimen. Both the RT2Gy×3f’x and RT9Gy×3f’x concurrent regimens markedly decreased the biodistribution of lenvatinib in the heart, liver, lung, spleen, and kidneys, which ranged from 31% to 100% for RT2Gy×3f’x, and 11% to 100% for RT9Gy×3f’x, compared to the sham regimen. The PK and biodistribution of lenvatinib can be modulated by simultaneous off-target irradiation and SBRT doses. The timing of lenvatinib administration with respect to RT, impacted the PK and biodistribution of the drug. Additionally, off-target and SBRT doses had a similar ability to modulate the effect of systemic therapy.

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“…3 When incorporated into DNA, 5FU is bound to the sugar backbone to form 5FUrd, 4 enhancing damage in radiation therapy. 5 It is also noteworthy that 18 F-5-fluorouridine is already known as a probe for measuring tissue proliferation and characterization of tumors in the PET (positron emission tomography) imaging technique. 6…”

Section: Introductionmentioning

confidence: 99%