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At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. They have been widely studied, especially with respect to their immunopotentiating properties, their ability to counteract the side effects of chemotherapeutic drugs, and their anticancer properties. However, the mechanism by which APS inhibit cancer and the issue of whether that mechanism involves the reversal of multidrug resistance (MDR) is not completely clear. The present paper describes an investigation of the effects of APS on P-glycoprotein function and expression in H22 hepatoma cell lines resistant to Adriamycin (H22/ADM). Methods H22/ADM cell lines were treated with different concentrations of APS and/or the most common chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine. Chemotherapeutic drug sensitivity, P-glycoprotein function and expression, and MDR1 mRNA expression were detected using MTT assay, flow cytometry, Western blotting, and quantitative RT-PCR. Results When used alone, APS had no anti-tumor activity in H22/ADM cells in vitro. However, it can increase the cytotoxicity of certain chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine, in H22/ADM cells. It acts in a dose-dependent manner. Compared to a blank control group, APS increased intracellular Rhodamine-123 retention and decreased P-glycoprotein efflux function in a dose-dependent manner. These factors were assessed 24 h, 48 h, and 72 h after administration. APS down regulated P-glycoprotein and MDR1 mRNA expression in a concentration-dependent manner within a final range of 0.8–500 mg/L and in a time-dependent manner from 24–72 h. Conclusion APS can enhance the chemosensitivity of H22/ADM cells. This may involve the downregulation of MDR1 mRNA expression, inhibition of P-GP efflux pump function, or both, which would decrease the expression of the MDR1 protein.

This study aimed to simultaneously determine mesalazine (5‐ASA) and its major metabolite N‐Ac‐5‐ASA in the plasma and to evaluate the impact of different food patterns on the relative bioavailability and pharmacokinetics of a single oral dose of 5‐ASA in healthy subjects. In this single‐dose, open‐label, 3‐period, 3‐treatment crossover study, the subjects received a single, oral dose of 500‐mg enteric‐coated mesalazine tablet together with either a low‐fat or a high‐fat breakfast or under fasting condition (reference). The pharmacokinetic parameters were determined by noncompartmental methods and analyzed with a linear mixed‐effect model. The geometric least squares mean ratio for the area under the plasma concentration–time curve from zero to infinity of N‐Ac‐5‐ASA was 1.05 (90% confidence interval [CI], 0.70‐1.58) for high‐fat/fasted condition and 1.06 (90%CI, 0.82‐1.36) for low‐fat/fasted condition. The least squares mean ratio of 5‐ASA was 0.86 (90%CI, 0.65‐1.14) for high‐fat/fasted condition and 0.78 (90%CI, 0.60‐1.02) for low‐fat/fasted condition. All P values were >.05. The mean maximum plasma concentration and the time to reach the maximum plasma concentration of N‐Ac‐5‐ASA were 2084 ng/mL, 8 hours; 2639 ng/mL, 11 hours, and 2409 ng/mL, 9 hours for fasted, high‐fat, and low‐fat, respectively. The values of 5‐ASA were 1950 ng/mL, 7 hours; 2869 ng/mL, 9 hours; and 2837 ng/mL, 8 hours for fasted, high‐fat, and low‐fat condition. 5‐ASA was well tolerated under all 3 conditions. Food delayed the absorption of 5‐ASA, especially a high‐fat meal. Therefore, enteric‐coated mesalazine tablets should be taken before meals to avoid causing patients slow response and any effect of food on its efficacy. [ABSTRACT FROM AUTHOR]