**3. P-gp**

P-gp is an adenosine triphosphatase (ATPase) energy-dependent, membranebound protein that belongs to the ABC efflux transporter family [35]. The ABCB1 gene, which is also known as the multidrug resistance 1 (MDR1), encodes P-gp and is responsible for cellular efflux of numerous drugs [36]. It is more prominent in various resistant human tumors, where it is believed to be the major factors responsible for multidrug resistant (MDR). P-gp-mediated transport of drugs is saturable, ATP-dependent, osmotically sensitive mechanism that generates a concentration gradient. In intestines, P-gp expressed in apical side of the epithelial cells where it pumps the drug back into the GI lumen resulting in fecal excretion. In liver, it presents in canalicular surface of hepatocytes to remove drug and metabolites from the interior of the cell. In brain, it is expressed in endothelial cells of blood brain barrier and prevented the entry of xenobiotics into brain. In kidney, it is expressed in proximal tubes of kidney to efflux drug into urine and in certain hematological cells to put drug back into circulation [37–40]. Higher expression of P-gp in excretory organs (liver and kidney) facilitates metabolism of substrate drugs via biliary excretion and renal elimination. As an efflux transporter, ABCB1 prevents intestinal absorption of orally administered drugs and limits its oral bioavailability. A broad range of clinically used drugs are substrate of P-gp, including anticancer agents (anthracyclines, vinca alkaloids, epipodophyllotoxins, methotrexate, and taxol) [41], cardiac drugs (digoxin and quinidine) [42], protease inhibitors (saquinavir, indinavir, and ritonavir) [43], immunosuppressants (cyclosporine) [44], and antibiotics (actinomycin D) [45].

## **4. Interplay between CYP3A and P-gp**

Various preclinical and clinical studies have postulated that both CYP3A enzyme and P-gp transporter display strong effects in modulation of oral drug bioavailability and elimination of numerous drugs. Both CYP3A and P-gp act in functional collaboration during the first-pass elimination of drug [46]. Extensive overlap exists between the substrate specificities and the tissue-specific expression patterns of P-gp and CYP3A, especially in the liver (hepatocytes) and intestine (enterocytes) [47, 48]. It has also been predicted that the orally administered drugs, which are dual substrates of P-gp and CYP3A, the back-transportation mechanism by P-gp in intestinal epithelial cells, are available for further CYP3A4-mediated metabolism within these cells resulting in massive first-pass effects in intestine [49]. The combined action of these two pathways was expected to be more efficient than the sum of their individual activities, resulting in synergistic effects of P-gp and CYP3A.

Two mechanistic frameworks have been suggested to support the possible synergistic action of P-gp and CYP3A in intestine. Under the first mechanism, P-gp acts to decrease the level of intracellular concentration of a substrate drug in *Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential… DOI: http://dx.doi.org/10.5772/intechopen.92712*

#### **Figure 2.**

*Potential functional relationships between P-gp and CYP3A4 in enterocytes.*

enterocytes, thus preventing possible saturation of the CYP3A enzyme by maintaining the drug within the linear range for metabolic activity. Under the second mechanism, the functional effects of P-gp, together with subsequent drug reuptake, allow the repetition of drug substrate, and therefore, probability of the drug to be metabolized increases by prolonged access to enterocyte CYP3A. The above cyclic repetition of drugs *per se* would itself increase the drug metabolism, even without considering saturating or nonsaturating conditions for CYP3A [50]. Based on above evidence, it is concluded that induction and inhibition of (intestinal) P-gp and CYP3A4 are important mechanisms underlying DDIs [51].

The hypothesis of synergistic collaboration between CYP3A and P-gp was clarified in a study that showed a dramatic increase in the systemic exposure of docetaxel and the risk of intestinal toxicity in P-gp<sup>−</sup>/<sup>−</sup>CYP3A<sup>−</sup>/<sup>−</sup> double knockout mice. After oral administration of docetaxel, 3-fold and 12-fold increases in bioavailability were observed in P-gp<sup>−</sup>/<sup>−</sup> and CYP3A<sup>−</sup>/<sup>−</sup> mice, respectively, in comparison with wild-type mice. However, when both of the primary detoxification systems were missing, that is, in P-gp<sup>−</sup>/<sup>−</sup>CYP3A<sup>−</sup>/<sup>−</sup> double knockout mice, bioavailability showed a disproportionate increase in >70-fold in comparison with wild-type mice [48].

Within the context described above, it is clear that drugs that are dual substrates for P-gp and CYP3A are highly susceptible to herb-drug interactions. Therefore, the consumption of herbs that modulate efflux transporters and CYP3A may cause clinically significant drug-herb interactions and alter drug bioavailability [13, 14]. The inhibitory effect of herbs on P-gp and CYP3A may result in increasing the drug concentration level in the plasma and tissues, leading to toxicity, whereas any inductive effect may result in lowering the concentration level, leading to loss of efficacy and/or treatment failure (**Figure 2**).

#### **5. Regulation of CYP3A and P-gp expression**

Pregnane X receptor (PXR) is a highly promiscuous nuclear hormone receptor, generally expressed on sites that are important to drug dispositions (e.g., small intestine, liver, and kidney). The human orthologue of PXR is also known as steroid and xenobiotics receptor (SXR) and is coded by NR 112. It has been reported that PXR regulates the expression of CYP3A and several other genes encoding protein and other enzymes, which involves in drug disposition including P-gp [52, 53]. Based on this evidence, Maglich et al. hypothesized that PXR plays a more important role in the regulation of drug metabolizing enzymes and drug transporters in the small intestines [54]. The observation that PXR regulates both CYP3A and P-gp provides further evidence for the argument that these proteins coordinately mediate detoxification of many xenobiotics during oral absorptions [46]. Synold et al. were the first to describe coregulation of drug metabolism and efflux via CYP3A and P-gp in liver and intestine by the human receptor PXR/SXR. Their results indicate that paclitaxel reduces its own oral bioavailability by activating the PXR and induces its own metabolism and biliary elimination [55].
