Decrease in plasma concentrations of antiangiogenic agent TSU-68 ((Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during oral administration twice a day to rats.
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 [(14)C]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.
Kitamura
Ryuichi
R
Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchicho, Tokushima 771-0194, Japan. r-kitamura@taiho.co.jp
Yamamoto
Yoshio
Y
Nagayama
Sekio
S
Otagiri
Masaki
M
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D000078183:Oxindoles; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011758:Pyrroles; D051381:Rats; D017207:Rats, Sprague-Dawley
D020533:Angiogenesis Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; C412603:orantinib