**9. Tyrosine kinase inhibitors**

The evidence of protein tyrosine kinase enzyme involvement in tumor development makes it novel targets for selective chemotherapy and thus target for rational design of drug development. Now protein kinases, especially tyrosine kinases, are being used as main targets for drug development related to malignancy, resulting in the high approval rate of various TKIs by the FDA [24, 107]. Imatinib was the first of its kind, which was introduced clinically, followed by various molecules such as gefitinib, erlotinib, sorafenib, afatinib, nilotinib, bosutinib, crizotinib, ponatinib, lapatinib, sunitinib, and dasatinib, and many more are in pipeline [108]. Although mechanism of action of these compounds is same, that is, competitive ATP inhibition at the catalytic binding site of tyrosine kinases, they differ from each other in the spectrum of targeted kinase activity, pharmacokinetic profile, and compoundspecific adverse effects [109]. These TKIs have been developed in oral formulations, are administered on a daily basis, and usually prescribed at a fixed dose. Although oral administration may be convenient for patients as it can reduce health care costs, improve quality of life of patients, and avoid heavy burden of day-stay infusion units, this practice also displays a disadvantage, in that the oral bioavailability of most of TKIs is highly dependent on their absorption through gastrointestinal tract and first-pass hepatic metabolism [25, 107].

Almost all TKIs are rapidly absorbed, and their maximum plasma concentration (Cmax) was achieved in 3–6 h after oral administration except sunitinib (6–12 h). Food intake has no significant effect on the absorption of imatinib, dasatinib, gefitinib, sorafenib, or sunitinib. However, the bioavailability of lapatinib and


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

#### **Table 3.**

*Substrate potential of TKIs with CYP3A4 and/or P-gp.*

nilotinib is increased pronouncedly with food intake. Almost all TKIs are high to plasma protein (>90%) and therefore extensively distribute into tissues resulting in large volume of distribution and prolong terminal half-life. Excretion of TKIs is predominantly through feces, and only a small fraction is eliminated with urine. Almost all TKIs are dual substrates of CYP3A4 (the most abundant CYP in the human liver and intestine) and P-gp efflux transporter, except sorafenib, vandetanib, bosutinib, ibrutinib, cabozantinib, regorafenib, and ruxolitinib, which are only substrate of CYP3A4, whereas vemurafenib and afatinib, which are effluxed by P-gp only [24, 108, 110–121]. **Table 3** summarizes the substrate potential of TKIs with CYP3A4 and/or P-gp.
