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

Abstract

ABSTRACT: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.

Identification of Human Liver Cytochrome P450 Isoforms Involved in Autoinduced Metabolism of the Antiangiogenic Agent (Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic Acid (TSU-68)

“…This similarity makes the extrapolation of in vivo results between rats and humans more reliable. Furthermore, our group's previous work with rats demonstrated that decreased plasma concentrations of TSU-68 resulted from the autoinduction (Kitamura et al, 2007). Overall, therefore, the human in vitro results obtained in this study and the in vivo finding in rats strongly support the idea that the clinically observed decrease in the plasma concentrations of repeatedly administered TSU-68 is attributed to autoinduction via CYP1A1/2.…”

“…Interestingly, this decrease occurred as early as the second dose of TSU-68 on day 1. In preclinical studies, TSU-68 administered to rats was shown to induce hepatic P450 activity, which was responsible for its metabolism (autoinduction), thereby markedly decreasing plasma concentrations of TSU-68 within a day (Kitamura et al, 2007). However, this finding provides no conclusive evidence that the clinically observed decrease is due to this autoinduction, because there are interspecies differences in P450 induction (Kern et al, 1997;Lu and Li, 2001;Martignoni et al, 2006).…”

CYP2C75-Involved Autoinduction of Metabolism in Rhesus Monkeys of Methyl 3-Chloro-3′-fluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-carboxylate (MK-0686), a Bradykinin B1 Receptor Antagonist

“…Unlike several reported autoinduction cases where the induced P450 enzymes dominated the total clearance of the compounds in either human or preclinical species (Gibson et al, 2005;Shimizu et al, 2006;Kitamura et al, 2007), MK-0686 was eliminated via both hydrolytic reactions and CYP2C75-mediated oxidation in rhesus monkeys. The contribution of the former pathways seemed to be equal to or greater than the latter for the total clearance of MK-0686 (Fig.…”

“…jpet.aspetjournals.org first two parameters is well precedented, tools for identifying important P450s are not readily available for preclinical species. Only limited efforts have been reported to investigate the P450 isozymes involved in autoinduction in dogs (Gibson et al, 2005) and rats (Kitamura et al, 2007). The remarkable reduction of systemic exposure of MK-0686 in rhesus monkeys after repeated oral administration presents the first report of autoinduction attributed to rhesus CYP2C75.…”

Hepatic Drug-Metabolizing Enzyme Induction and Implications for Preclinical and Clinical Risk Assessment

“…There are, however, other examples where induction of DMEs in rats is also observed in humans. For example, TSU-68, an experimental receptor tyrosine kinase inhibitor, showed autoinduction of CYP1A in rats (Kitamura et al 2007;Kitamura, Matsuoka et al 2008) and humans (Kitamura, Asanoma et al 2008;Sessa et al 2006).…”