Currently, more than one fourth of all anticancer drugs are developed as oral formulations, and it is expected that this number will increase substantially in the near future. To enable oral drug therapy, adequate oral bioavailability must be achieved. Factors that have proved to be important in limiting the oral bioavailability are the presence of ATP-binding cassette drug transporters (ABC transporters) and the cytochrome P450 enzymes. We discuss the tissues distribution and physiological function of the ABC transporters in the human body, their expression in tumors, currently known polymorphisms and drugs that are able to inhibit their function as transporter. Furthermore, the role of the ABC transporters and drug-metabolizing enzymes as mechanisms to modulate the pharmacokinetics of anticancer agents, will be reviewed. Finally, some clinical examples of oral drug modulation are discussed. Among these examples are the coadministration of paclitaxel with CsA, a CYP3A4 substrate with P-glycoprotein (P-gp) modulating activity, and topotecan combined with the BCRP/P-gp transport inhibitor elacridar. Both are good examples of improvement of oral drug bioavailability by temporary inhibition of drug transporters in the gut epithelium.
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