Received for publication November 29, 2006.
Revised May 2, 2007.
Accepted for publication June 11, 2007.

Decrease in plasma concentrations of antiangiogenic agent TSU-68 (SU6668) during oral administration twice a day to rats

Abstract

TSU-68 (SU6668) is a new drug under investigation that inhibits receptor tyrosine kinases involved in tumor angiogenesis. In clinical pharmacokinetic studies, lower plasma concentrations of orally administered TSU-68 are observed after the second dose given within 12 h after the first dose. We examined the cause of this observation through in vivo and ex vivo approaches using rats in which a rapid decrease in the exposure was shown as in humans. In rats, the AUC after the second dose was decreased to 26% of that after the first dose during administration of TSU-68 (200 mg/kg) twice a day. Plasma clearance of TSU-68 intravenously administered after the oral administration 12 h beforehand was 1.5-fold higher and the half-life was 2-fold shorter compared with those after the single intravenous administration. The amount of absorbed TSU-68, as indicated by the radioactivity totally excreted in the bile and urine following oral administration of [¹⁴C]TSU-68, was unchanged by the prior oral administration. These results demonstrate that administered TSU-68 causes an increase in its elimination but not a decrease in its absorption after the subsequent administration. Furthermore, rat liver taken 12 h after administration of TSU-68 exhibited 6-fold higher activity of its microsomal oxidase than untreated liver. This result suggests that TSU-68 induced its own oxidative metabolism (i.e., autoinduction). In conclusion, the decrease in plasma concentrations of TSU-68 during the administration twice a day to rats was due to the rapid autoinduction. The same mechanism is probably at work in the clinical setting.

Key words: anticancer agents, cytochrome P450, hepatic elimination, induction, liver microsomes, oral absorption, UDP glucuronyltransferases

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