**11. Flavonoids and TKI interaction**

Compounds that are capable of inhibiting the activity of tyrosine kinase receptors (RTKs) are expected to display antiproliferative properties. Various *in vitro* and *in vivo* studies suggested that most of the flavonoids quercetin, genistein, hesperidin, and naringenin have TKI properties, which play a significant role in its anticancer effects [135–138]. Due to antiproliferative properties, flavonoids can be use along with conventional TKIs in clinical practice and therefore it definitely raise concern of pharmacokinetic interaction. So, it is understood that similar to

### *Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential… DOI: http://dx.doi.org/10.5772/intechopen.92712*

conventional medicines, flavonoids act as dual modulators of CYP3A4 and P-gp, which may produce significant effects on the disposition kinetics of TKIs. In spite of that, limited data are available relevant to interaction of flavonoids with TKIs in the literature. St. John's wort that contains numerous flavonoids was found to increase imatinib clearance by 43% and decrease its AUC and Cmax by 30 and 29%, respectively [139, 140] in human subjects. Similarly, St. John's wort may also decrease the plasma concentration of dasatinib, and its use is discouraged in patients receiving it [141]. Genistein (isoflavone) when administered for 15 days significantly decreased the Cmax and AUC of imatinib, whereas its single dose did not produce any effects in rats [142]. Silybin, a constituent of silymarin, also decreased the AUC of imatinib after multiple dose administration (15 days) in rats [143]. However, apigenin in single dose increased the AUC of imatinib but decreased it in multiple dose administration (15 days) in rats [144], which suggests that apigenin may act as enzyme inhibitor in single dose and become inducer after long-term administration. Epigallocatechin-3-gallate also decreased the Cmax and AUC of sunitinib after single dose administration in rats [145]. However, Bas 100, a novel mechanism-based CYP3A4 inhibitor, isolated from grapefruit juice increased 2.1-fold AUC of erlotinib after single dose administration [146]. Similar


#### **Table 4.**

In vivo *pharmacokinetic interaction of flavonoids or flavonoids containing herbal constituents with TKIs.*

effects were produced by the intake of 240 ml of grapefruit juice (an inhibitor of CYP3A4 and P-gp), which are shown to increase the nilotinib AUC by 60%, and thus, coadministration of nilotinib with grapefruit juice is not recommended [147]. Additionally, a case study showed that patients who had already developed resistance to gefitinib treatment become responsive after the withdrawal of all CAMs [148]. **Table 4** summarizes the pharmacokinetic interaction of flavonoids or flavonoids containing herbal constituents with TKIs in both experimental animals and clinical studies.
