The oral route for the administration of cytotoxic drugs: strategies to increase the efficiency and consistency of drug delivery

There is an increasing interest to administer cytotoxic drugs to patients b y the oral route. Quality of life issues, treatment advantages and pharmaco -economics are major arguments in favor of oral therapy. However, low or mo derate bioavailability in combination with considerable interpatient variab ility are frequently observed which may reduce the feasibility of the oral route for this class of drugs with a generally narrow therapeutic window. U ntil recently, investigators focused on absorption enhancers which slightly damage the intestinal surface such as salicylates, methylxantines and surf actants to improve the oral bioavailability of drugs. To date, a shift can be seen towards more subtle mechanisms to enhance the absorption. This revi ew article focuses on two important mechanisms that determine the oral bioa vailability of cytotoxic drugs. These include the presence of drug transpor ters in the intestinal epithelium pumping drugs into the intestinal lumen, such as MDR1 type P-glycoproteins, and first-pass elimination by cytochrome P450 isoenzymes (e.g. 3A4 and 3A5) or other enzymes in the intestines and/ or liver. Currently preclinical and clinical studies are being performed to explore the feasibility of blocking these transporters/enzymes in order to achieve higher and less variable systemic drug levels after oral dosing. T his review gives an update of the results of these studies. It is concluded however, that further research to unravel the processes involved in oral d rug uptake is warranted to make the oral route a more efficient and consist ent way of drug administration.