**1. Introduction**

Due to common belief that natural medicines are much safer than synthetic one, the use of complementary and alternative medical therapies (CAMs) has become a

common trend around the world. It can be used either alone or in combination with prescription medicines [1]. According to an estimate of World Health Organization (WHO), approximately 80% of the developing countries' population relies on CAMs for their primary healthcare needs [2, 3]. CAMs have been also become popular around the developed countries, and this has led to a tremendous growth in international herbal drug market for the last 15years [4–6]. Consumption of CAMs is more pronounced in patients diagnosed with cancer or human immune virus (HIV) infection, especially with regard to various antidepressant and energy treatments to cope with their mental and physiological instability [7]. The bioavailability and the distribution characteristics are the key factor for the therapeutic effects of pharmaceuticals at their site(s) of action in the tissue [8]. Due to higher consumption of CAMs (herbal extracts and dietary supplements) with prescription medicines, there is a growing awareness that herbal remedies and/or phytoconstituents may affect the bioavailability and disposition characteristics of conventional pharmaceuticals [9]. The medical and scientific literature supported by *in vitro* and *in vivo* laboratory studies including preclinical and clinical trials suggested that the co-administration of natural products or its phytoconstituents may affect the metabolism and bioavailability of prescription drugs, which significantly increasing the risk of serious (clinical) adverse reactions or therapeutic failure. The primary mechanisms underlying the herb-drug interactions involve either the induction or the inhibition of intestinal drug efflux pumps (including efflux proteins, such as P-gp and MRPs) and the intestinal and hepatic metabolism mediated by cytochrome P450 enzymes (CYP3A) [10–12]. Hence, the consumption of herbs that can modulate efflux proteins and/or CYP3A may cause clinically relevant herb-drug interactions and alter drug bioavailability [13, 14]. Any inhibitory effect of herbal extracts/constituents on efflux proteins and/or CYP3A may result in high exposure of substrate drugs in plasma and tissue and lead to toxicity, whereas any inductive effect may cause low exposure, leading to a decrease in efficacy and treatment failure.

The biological effects produced by CAMs are due to the presence of various classes of phytochemicals present there, that is, alkaloids, flavonoids, terpenoids, carotenoids, polyketides, and phenylpropanoids. Among them, flavonoids have attracted much interest due to their numerous pharmacological activities and health benefit in the form of their antioxidant, anti-inflammatory, antimutagenic, antibacterial, antiangiogenic and enzyme modulatory, antiallergic, and anticancer activities [15, 16] and become the main components of herbal products where it presents in the form of quercetin, genistein, hypericin, kaempferol, and silibinin. There is accumulated evidence in the literature, which confirms that flavonoids modulate drug metabolism. Modulation may happen by either (1) altering the expression and/or activity of P450 enzymes, (2) affecting the P-gp-mediated cellular efflux of drugs, and/or (3) inhibiting the intestinal glucuronidation of the drug. This evidence confirms that the consumption of flavonoids or flavonoid-containing dietary supplements with conventional pharmacotherapeutic regimens should need to be examined to avoid drug-flavonoid interactions [17–21].

Among the novel classes of anticancer drug development, small molecule tyrosine kinase inhibitors (TKIs) currently represent one of the most promising and rapidly expanding groups. Almost 25 TKIs (mostly in oral dosage form) have been already approved by international drug agencies, >130 are being evaluated in different phases of clinical trials, and many more are in various stages of development [22, 23]. Most of TKIs are primarily metabolized by CYP3A4 and also interact with P-gp and/or Breast Cancer Resistance Protein (BCRP) where it serves as both substrates and inhibitors. Considering the dual roles of TKIs on both CYP3A4 and drug transporters (P-gp, BCRP) and its influence in drug disposition, the potential *Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential… DOI: http://dx.doi.org/10.5772/intechopen.92712*

**Figure 1.**

*Schematic layout for prediction of flavonoids in modulation of CYP3A enzyme and P-gp transporter and its influence on disposition of TKIs.*

of TKI-drug interactions is an important consideration [24, 25]. In addition, most TKIs are being used orally and prescribed for long duration along with other medications, which may result in significant drug-drug interactions (DDI). This review provides a comprehensive overview of the potential role of flavonoids in modulation of CYP3A enzyme and P-gp transporter and their possible influence on bioavailability and disposition of tyrosine kinase inhibitors (**Figure 1**).
