A novel taxane (IDN 5109), originally selected for its ability to overcome P-glycoprotein-mediated drug resistance, is characterized by an improved preclinical profile in terms of efficacy and tolerability. Because P-glycoprotein may critically influence intestinal absorption and oral bioavailability of taxanes, the purpose of the study was to evaluate the bioavailability, the pharmacokinetic behavior, and the antitumor activity of the new taxane after oral administration. A comparative study of antitumor activity of Taxol and IDN 5109 given orally was performed in a human breast carcinoma model, MX-1, which is highly responsive to i.v. treatment with both of the taxanes. In contrast to Taxol, which was completely ineffective after administration to MX-1-bearing mice, oral IDN 5109 exhibited an activity comparable with that of i.v. treatment (ie., 100% cures). Again, the maximal tolerated doses were comparable (90 mg/kg, every 4 days for four doses) after i.v. and oral treatment. Three other tumor models (LoVo, IGROV/DDP, and U87) with a variable sensitivity to the drug were used to compare the antitumor effects of i.v. and oral treatment with IDN 5109. The efficacy after oral administration was only slightly lower than that found after i.v. treatment at equivalent doses; but optimal effects were comparable likely as a consequence of the long (>6 h) terminal half-life of oral IDN 5109. The bioavailability of IDN 5109 assessed by comparing area-under-the-curve values after oral and i.v. administrations was approximately 50%. The oral efficacy of the novel taxane, likely related to the inability of the P-glycoprotein to recognize the drug, which allowed an adequate intestinal absorption, is a unique feature among the taxanes and may represent a pharmacological breakthrough in their clinical use.