TY - JOUR T1 - Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((<em>Z</em>)-5-[(1,2-Dihydro-2-oxo-3<em>H</em>-indol-3-ylidene)methyl]-2,4-dimethyl-1<em>H</em>-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1611 LP - 1616 DO - 10.1124/dmd.106.014068 VL - 35 IS - 9 AU - Ryuichi Kitamura AU - Yoshio Yamamoto AU - Sekio Nagayama AU - Masaki Otagiri Y1 - 2007/09/01 UR - http://dmd.aspetjournals.org/content/35/9/1611.abstract N2 - TSU-68 ((Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) 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 area under the concentration-time curve 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 12 h after oral administration 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. The American Society for Pharmacology and Experimental Therapeutics ER -