Background and purpose: This study investigated whether the "RT-PK" phenomenon, referring to radiation therapy's effects on the pharmacokinetics of chemotherapeutic agents, occurs with cabozantinib, a multikinase inhibitor, after radiotherapy and investigated the underlying mechanisms.
Method: A quantitative liquid chromatography-tandem mass spectrometry method was developed for cabozantinib. Sprague-Dawley (SD) rats were irradiated with X-rays, and changes in cabozantinib distribution and concentration in the blood and excreta were monitored. The RT-PK phenomenon was confirmed, and further studies examined liver injury and alterations in primary metabolic enzymes in rats and HepG2 cells using hematoxylin and eosin staining, flow cytometry, Western blot, quantitative reverse transcription polymerase chain reaction, and serum biochemical analysis. The mRNA expression of IL6/STAT3 and PXR was also determined.
Results: X-ray exposure increased the area under the drug-time curve (AUC0-t) of cabozantinib by 3.6-fold, and excretion of the drug in the feces was 73 % lower in irradiated rats. Hematoxylin and eosin staining showed hepatocyte and interstitial edema, and serum Alanine transaminase and aspartate transaminase contents were decreased. Radiation induced redox imbalance, increased reactive oxygen species and apoptotic markers, and reduced superoxide dismutase and GSH/GSSG contents. As indicated by western blotting and RT-qPCR, the activation of the IL-6/STAT3 pathway reduced PXR expression, leading to decreased levels of CYP450 3A4, the key enzyme that metabolizes cabozantinib.
Conclusions: Radiation increased reactive oxygen species, activated the IL-6/STAT3 pathway, and inhibited PXR, thereby reducing CYP450 3A4 expression. These changes led to altered cabozantinib metabolism and the "RT-PK" phenomenon.
Keywords: Cabozantinib; Endoplasmic reticulum stress; IL-6/STAT3; Radiotherapy–pharmacokinetics phenomenon; Reactive oxygen species.
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