Pharmacokinetics and Metabolism in Mice of IDN 5390 (13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a New Oral C-seco-Taxane Derivative with Antiangiogenic Property Effective on Paclitaxel-Resistant Tumors
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-tubuli...
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Published in | Drug metabolism and disposition Vol. 34; no. 12; pp. 2028 - 2035 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.12.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.106.012153 |