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.Limited bioavailability is mainly due to: 1) cytochrome P450 (CYP, especially CYP3A) activity in gut wall and liver, and 2) drug transporters, such as P-gp and breast cancer resistance protein (BCRP, ABCG2) in gut wall and liver.Shared substrate drugs are affected by the combined activity of these systems.We have developed novel and in part humanized systems that allow reliable translation of preclinical results to the clinic (Drug Metab Dispos 2005;33:892-5 & J Clin Invest 2007; 117:3583-92).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 (Cell 1994;77:491; PNAS 1997;94:2031; Lancet 1998;352:285; J Clin Oncol 2001; 19:1160-6).This work revealed, however, that apart from P-gp other drug-transporting systems and CYP effects also determine overall oral drug uptake.Indeed, we demonstrated that blockade of ABCG2 profoundly increased the oral bioavailability oftopotecan in mice and man (J Natl Cancer Inst 2000;92:1651-6 & J Clin Oncol 2002;20:2943-50).