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

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 ␤-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 antitumor activity.

Taxane's Substituents at C3′ Affect Its Regioselective Metabolism: Different in Vitro Metabolism of Cephalomannine and Paclitaxel

“…The structure of M2 (RT, 10.9 min) could not be ascertained from the fragment ions. In parallel with hydroxylation sites of paclitaxel and some other taxanes (Cresteil et al, 2002;Frapolli et al, 2006), we propose C6␣ as the possible hydroxylation site for M2 (Fig. 1).…”

“…Meanwhile, the primary monooxygenases changed from CYP2C8 to CYP3A4 (Cresteil et al, 2002;Taniguchi et al, 2005). Interestingly, when both phenyls at C3Ј of C13 side chain were replaced by the alkyl or alkenyl group, the major hydroxylation site was again moved from tert-butyl back to the isobutyl or isobutenyl group, such as SB-T-1102, SB-T-1214, SB-T-1216 (Gut et al, 2006), and IDN5390 (Frapolli et al, 2006). All of these results suggested that substituents at C3Ј determined taxane metabolism with regard to the site of hydroxylation and the P450 isoform implicated.…”

“…The superior antitumor activity of paclitaxel, however, is undermined by limitations such as multidrug resistance, poor aqueous solubility, poor oral bioavailability, and toxicities (Frapolli et al, 2006). It is generally recognized that poor oral bioavailability of paclitaxel results from its poor solubility (Singla et al, 2002) and P-glycoprotein efflux (Sparreboom et al, 1997).…”

CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183)

“…1B) to the CYP3A4-catalyzed hydroxylation at tert-butyl of the side chain (Cresteil et al, 2002;Taniguchi et al, 2005). It is interesting to note that when both phenyl and benzamide at C3Ј of C13 side chain were replaced by N-␣-tert-butyloxycarbonyl amino group and an alkyl or alkenyl group, respectively, the major hydroxylation site was again moved from tert-butyl to the alkyl group (Frapolli et al, 2006;Gut et al, 2006). Zhang et al (2008) investigated how different substitutes at the C3Ј position of taxane analogs affected its metabolism with cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3Ј position.…”

“…The compound is a C-4 methyl carbonate analog of paclitaxel that contains additional modifications in the side chain where the two phenyl groups of paclitaxel were replaced by t-butyl groups (Bröker et al, 2007). BMS-275183 exhibited good oral bioavailability in both rat and dog and showed antitumor activity comparable with intravenous paclitaxel (Frapolli et al, 2006).[ 14 C]BMS-275183 was metabolized to oxidative metabolites in liver microsomes of animals and humans and in bile duct-cannulated rats Kim-Kang et al, 2002). Only trace amounts of conjugated metabolites were detected in rat bile.…”