Received for publication July 25, 2006.
Revised September 7, 2006.
Accepted for publication September 7, 2006.

Pharmacokinetics and metabolism in mice of IDN 5390, a new oral C-seco-taxane derivative with antiangiogenic property effective on paclitaxel-resistant tumors

Abstract

IDN 5390 is a new taxane, derived from 7,8-C-seco-10-deacetylbaccatin, selected for its ability to inhibit angiogenesis, mainly by acting on endothelial cell motility and for its selective activity on class III beta-tubulin. In vivo IDN 5390 shows activity against paclitaxel-sensitive and resistant tumors when administered on a prolonged, continuous dosage schedule. We studied the pharmacokinetics and bioavailabilty of the drug in mice after single and repeated oral treatment. IDN 5390 was rapidly absorbed after oral administration, with good bioavailability (43%). After intravenous injection, it was extensively distributed in tissue, mainly the liver, kidney and heart, with low but persistent levels in brain. The kinetics appear dose-dependent with clearance of respectively 2.6, 1.4 and 0.9 L/kg at 60, 90 and 120 mg/kg, and half-life 24, 36 and 54 minutes. After prolonged daily oral doses given for two weeks, we found that there was a decrease in drug availability, i.e. the AUC value after p.o. daily administration on day 14 was two fold lower than that at day 1. Metabolism plays a major role in elimination of the drug, and at least 12 metabolites were identified in feces and urine. The percentage excreted as metabolites after an oral dose (42%) was higher than after the i.v. dose (33%), suggesting a first-pass effect. Four metabolites were found in plasma at detectable levels, one of them, with restored taxane scaffold, is a species three times more potent than IDN 5390, possibly contributing to the observed antitumor activity.

Key words: anticancer agents, bioavailability, mass spectrometry, metabolite identification, oral absorption, pharmacokinetics

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