**12. Conclusions**

The CYP3A enzyme accounts approximately 30% of hepatic and more than 70% of intestinal CYP activity. P-gp efflux protein is encoded by ABCB1 gene (MDR1) and is responsible for cellular efflux of numerous drugs. PXR regulates both CYP3A and P-gp and coordinately mediates detoxification of many xenobiotics during oral absorptions. The flavonoid constituent-mediated modulation of CYP3A and P-gp is the main mechanism through which the bioavailability and disposition of conventional drugs are regulated. The synergistically modulation of CYP3A and P-gp by flavonoids may increase the potency of chemotherapeutic drugs. Moreover, it increases the permeability of drugs in brain and reduces the MDR in cancer chemotherapy. Most of the TKIs are oral dosage formulations and also dual substrates of CYP3A and P-gp, so the risk of pharmacokinetic interactions with flavonoids is expected on concurrent administration. Therefore, there is a compelling need to study the cellular and molecular mechanisms involved in the flavonoid-mediated modulation of CYP3A and P-gp and their expected impact on the exposure and disposition of TKIs. Results from some experimental and clinical studies have confirmed the interaction between TKIs and flavonoids, but these unwanted clinical consequences in cancer patients have not been elaborated. However, even small changes in drug metabolism and pharmacokinetics of TKIs may lead to therapeutic failure or toxicity in cancer patients. Nevertheless, it is a challenging task to determine the clinical effects of the DDI due to the large interpatient variability in the pharmacokinetics of the TKIs.
