**8.29 Expression and its over-expression, advantage and drawback**

The expression of the P-gp is mainly found in all parts of the body by acting as a protective shield from the entry of the toxins and the xenobiotics. Their action is unavoidable in the Blood brain barrier, blood placental barrier and blood testes barrier but when concentration on the therapeutic aspect of the drugs the absorption of the drugs through the intestinal is retarded due to the expression of the P-gp in the intestinal lumen, not only in the lumen part though their presence are predicted all over the body but their expression is more in the diseased cells mainly the cancer cells. The plasma membrane of the intestinal epithelial cells pumps back the drug which enters into it and which are recognised as the substrate and are excreted [90–92]. Higher levels are seen in the biliary epithelium, proximal tubules of the kidney and the drugs are seen in the bile and the urine. For inhibiting the role of the P-gp the P-gp inhibitors are developed. Though the inhibitors shows the action when checked in preclinical studies but their action retards when come into the clinical trials. The progress report of the inhibitors are explained in **Figure 1**. The failure in the therapeutic efficacy with the cancer treatment is mainly due to the over-expression of P-gp.

#### **8.30 Cancer and drug resistance**

In 1940s: first cancer chemotherapy trails begin.

In 1970s: Mammalian cells showed resistance to the anticancer agents recurrently exhibited cross-resistance to drugs which are structurally and functionally dissimilar.

Multidrug resistance was a foremost problem in the cancer chemotherapy because it involved resistance to some of the commonly used and the first line anticancer drugs.

In 982s: Multidrug resistance was shown in most of the cases which results in decline in the intercellular drug accumulation, apparently as a result of altering in the plasma membrane. In many multidrug resistant cell lines, the resistance was found to correlate with over expression of a 170-kDa membrane protein (P-gp) [93, 94].

Why to study Multidrug resistance?


**Figure 1.** *P-gp inhibitor development timeline. The progress report of the inhibitors.*

