**8. Significance of flavonoids as P-gp and CYP3A inhibitors**

Various experimental and clinical studies confirmed that flavonoids produce antioxidant, anti-inflammatory, and anticarcinogenic effects. Studies also confirmed that these effects were attributed due to their inhibitions of efflux transporter enzyme (P-gp) and/or drug metabolizing enzyme (CYP3A). Therefore, flavonoids as P-gp inhibitor may use with other chemotherapeutic drugs for cancer treatment [100]. Occurrence of P-gp protein in various body tissues affects the absorption, distribution, metabolism, and excretion of drugs. Therefore, the dual effect of anticarcinogenic and P-gp modulation may synergistically act for the treatment of cancer [101]. The chemotherapeutic treatment of metastatic brain tumors is limited due to its low distribution in brain tissue by blood brain barrier and blood-cerebrospinal fluid barrier. P-gp is presented in the apical membranes of these cells, and flavonoids can improve the permeation of chemotherapeutic drugs by inhibiting the P-gp-mediated efflux [102]. Flavonoids can be used as nontoxic P-gp and/or CYP3A inhibitors and by its coadministration could improve the bioavailability of poorly unavailable drugs, especially for anticancer drugs, by interfering its clearance or inhibiting its metabolism [103]. P-gp presents in bile canaliculi and kidney suggested that it can also play a role in biliary and renal elimination of drugs. Coadministration of flavonoids (as P-gp inhibitors) can reduce the clearance of anticancer drugs, for example, vinblastine, doxorubicin, and irinotecan [104, 105]. Flavonoids can also play an important role in reversal of MDR in cancer chemotherapy. P-gp-associated MDR is a serious concern for limitation of cancer treatment. P-gp occurrence in tumor cell has been extensively characterized, and its overexpression has been confirmed during relapse. Therefore, it can be concluding that P-gp inhibitors (flavonoids) can potentially reverse the MDR during cancer chemotherapy [106].
