Abstract
IDN 5390 (13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III) 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 β-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 a clearance of 2.6, 1.4, and 0.9 l/kg at, respectively, 60, 90, and 120 mg/kg, and a half-life 24, 36, and 54 min. After prolonged daily oral doses given for 2 weeks, we found that there was a decrease in drug availability; i.e., the area under the concentration-time curve value after p.o. daily administration on day 14 was 2-fold lower than that on 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 that 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 3 times more potent than IDN 5390, possibly contributing to the observed anti-tumor activity.
Footnotes
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The generous contribution of the Italian Association for Cancer Research is gratefully acknowledged.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012153.
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ABBREVIATIONS: IDN 5390, 13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III; IDN 5517, 13-(N-Boc-β-isobutyl-isoserinoyl)-9-O-methyl-C7,8-seco-10-deacetylbaccatin III; P-gp, P-glycoprotein; AUC, area under the concentration-time curve; Cmax, maximum plasma concentration; Tmax, time of Cmax; CL, clearance; Vd, volume of distribution; t1/2, half-life; F, bioavailability; IS, internal standard; HPLC, high-performance liquid chromatography; UDPGA, UDP-glucuronic acid; LC/MS/MS, liquid chromatography/tandem mass spectrometry; NRS, NADPH regenerating solution.
- Received July 20, 2006.
- Accepted September 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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