Modulation of oral bioavailability of anticancer drugs: from mouse to man.

Abstract

Oral bioavailability of many anticancer drugs is poor and highly variable. This is a major impediment to the development of new generation drugs in oncology, particularly those requiring a chronic treatment schedule, a.o. the farnesyltransferase inhibitors. Limited bioavailability is mainly due to: (1) cytochrome P450 (CYP) activity in gut wall and liver, and (2) drug transporters, such as P-gp in gut wall and liver. Shared substrate drugs are affected by the combined activity of these systems. Available preclinical in vitro and in vivo models are in many cases only poorly predictive for oral drug uptake in patients because of a.o. interspecies differences in CYP drug metabolism and intestinal drug-transporting systems. Clearly, novel systems that allow reliable translation of preclinical results to the clinic are strongly needed. Our previous work, also using P-gp knockout (KO) mice, already showed that P-gp has a major effect on the oral bioavailability of several drugs and that blockers of P-gp can drastically improve oral bioavailability of paclitaxel and other drugs in mice and humans (Schinkel et al., Cell 77 (1994) 491; Sparreboom et al., Proc. Natl. Acad, Sci. USA 94 (1997) 2031; Meerum Terwogt et al. Lancet 352 (1998) 285). This work revealed, however, that apart from P-gp other drug-transporting systems and CYP effects also determine overall oral drug uptake. The taxanes paclitaxel and docetaxel are considered excellent substrate drugs to test the concept that by inhibition of P-gp in the gut wall and CYP activity in gut wall and/or liver low oral bioavailability can be increased substantially. In current studies we focus on the development of chronic oral treatment schedules with these drugs and on other drug transport systems that may play a significant role in regulation of oral bioavailability of other classes of (anti-cancer) drugs. The current review paper describes the background and summarizes our recent results of modulation of oral bioavailability of poorly available drugs, focused on drug transport systems and CYP in gut wall and liver.