**3.1 P-gp effects on doxorubicin's Pharmacokinetics aspect**

Doxorubicin is poorly absorbed through GI with low bioavailability (approximately 5%) after orally taken, due to its instability in stomach acidic pH and CYP450 biotransformation in liver. In addition, doxorubicin can induce cytotoxicity in normal tissue. Currently, doxorubicin is commercially available for cancer treatment in injection dosage form. Due to its lipophilicity, doxorubicin moves through plasma membrane into the cells via passive diffusion, and its extent of tissues/cellular permeation and cellular retention can be limit by the existence of efflux transporters particularly P-gp. Apparently, doxorubicin is extensively distributed to several organs such as liver, heart, kidney after injection. Being the efflux transporters, P-gp has a significant impact on doxorubicin distribution to certain target tissues such as brain, testes [109, 110]. Certain P-gp inhibitors such as PSC-833, piperine capsaicin, resveratrol, silymarin and quercetin were reported their influence on the pharmacokinetics and tissue distribution of doxorubicin in animal models [85, 110]. Capsaicin was reported to significantly increase the extent of doxorubicin accumulation in mice brain after iv injection probably through inhibition of P-gp at blood brain barrier [110]. In addition, piperine and capsaincin,

through P-gp inhibition, reduced drug excretion into bile and urine, leading to increased drug levels in liver and kidney [110].

## **3.2 P-gp effects on doxorubicin's Pharmacodynamic aspects**

Critically, overexpression of P-gp on the plasma membrane of cancer cells is a major determinant in preventing intracellular doxorubicin accumulation up to its cytotoxic level. Doxorubicin resistant cancer cells clearly display significant lower intracellular doxorubicin retention with more tolerable to doxorubicin exposure than their parental sensitive cells [65, 66]. Thus, P-gp can be a potential therapeutic target for either MDR reversal or bio-enhancing effect in cancer therapy. The presence of P-gp modulators clearly demonstrates their abilities to restore doxorubicinmediated killing effect in various cancer cells by increasing intracellular level of doxorubicin [66, 111]. Several plant-based compounds such as limonin, quercetin, resveratrol, curcumin and rhinacanthin-C at their non-cytotoxic concentration have been reported to significantly enhance doxorubicin-mediated cytotoxicity in various cancer resistance cells through modulation of P-gp function [66, 112]. These phytochemical P-gp modulators may suppress P-gp function either by direct inhibition of activity or down-regulation of protein expression.

Moreover, the influence of P-gp on clinical resistance to doxorubicin-based treatment has been reported in cancer patients [113–116]. In order to improve drug efficacy and patient tolerability, several approaches targeting at the P-gp function and expression have been introduced to increase cellular doxorubicin drug level and restore drug sensitivity without the need of higher concentration or additional chemotherapeutic drugs in the therapeutic regimen.
