title: 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.
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 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 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.
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Frapolli
authors.forename: E
authors.initials: E
authors.lastname: Marangon
authors.forename: M
authors.initials: M
authors.lastname: Zaffaroni
authors.forename: T
authors.initials: T
authors.lastname: Colombo
authors.forename: C
authors.initials: C
authors.lastname: Falcioni
authors.forename: R
authors.initials: R
authors.lastname: Bagnati
authors.forename: M
authors.initials: M
authors.lastname: Simone
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.forename: C
authors.initials: C
authors.lastname: Manzotti
authors.forename: G
authors.initials: G
authors.lastname: Fontana
authors.forename: P
authors.initials: P
authors.lastname: Morazzoni
authors.forename: M
authors.initials: M
authors.lastname: Zucchetti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005243:Feces / Q000737:chemistry; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D017239:Paclitaxel; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; C459840:IDN 5390; D043823:Taxoids; D017239:Paclitaxel