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)

Kitamura, Reiko; Asanoma, Hisae; Nagayama, Shigeya; Otagiri, Masaki

doi:10.1124/dmd.107.019877

Cited by 14 publications

(9 citation statements)

References 29 publications

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“…Along with the PAH chemical class, TSU-68, an angiogenesis inhibitor, is an example of a drug candidate that has been linked to autoinduction of CYP1A in humans and rats, resulting in increased clearance (Kitamura et al, 2007, 2008). Other CYP1A inducers, such as TCDD and omeprazole, are not substrates for the enzyme, but nonetheless enhance its expression and activity (Ma and Lu, 2007).…”

Section: Discussionmentioning

confidence: 99%

AhR activation underlies the CYP1A autoinduction by A-998679 in rats

Liguori¹,

Lee²,

Liu³

et al. 2012

Front. Gene.

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Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 [3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl) benzonitrile], was shown to enhance its own clearance via induction of Cyp1a1 and Cyp1a2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound's plasma AUC decreased at 30 mg/kg (95%) and 100 mg/kg (80%). Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of Cyp1a, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR) in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces Cyp1a1 and Cyp1a2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons (PAHs), may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A-related mechanisms of drug metabolism and toxicity.

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Section: Discussionmentioning

confidence: 99%

AhR activation underlies the CYP1A autoinduction by A-998679 in rats

Liguori¹,

Lee²,

Liu³

et al. 2012

Front. Gene.

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“…The induction of FT metabolism by TSU-68 could be a reason for the decreased AUC of FT in group A, as CYP1A2 has been reported to have a minor role in the metabolism of FT to 5-FU (Komatsu et al , 2000), and TSU-68 has the potential to induce CYP1A2 (Kitamura et al , 2008). The effects of TSU-68 on plasma exposure to CDHP and Oxo cannot be denied; however, TSU-68 had no effect on plasma exposure to 5-FU, the active ingredient of S-1.…”

Section: Discussionmentioning

confidence: 99%

Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer

et al. 2013

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Background:This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.Methods:Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).Results:Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.Conclusion:Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.

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“…5,6) TSU-68 undergoes hydroxylation by CYP1A in human liver microsomes and also induces CYP1A1 and CYP1A2 in human hepatocytes. 7) This autoinduction profile leads to the clinical observation that plasma concentrations of TSU-68 are decreased after repeated administration of 200 mg/m 2 TSU-68. 8,9) It is notable that the decrease in the concentrations already occurs after the second dose on Day 1.…”

Section: Introductionmentioning

confidence: 95%

Time-dependent Induction of Rat Hepatic CYP1A1 and CYP1A2 Expression after Single-dose Administration of the Anti-angiogenic Agent TSU-68

Kitamura

Matsuoka

Nagayama

et al. 2008

Drug Metabolism and Pharmacokinetics

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The anti-angiogenic agent TSU-68 is known to rapidly induce cytochrome P450 activity responsible for its own hydroxylation in rats. In this study, we identified CYP1A1 and CYP1A2 as the TSU-68-induced P450 and temporally characterized the rapid induction of these isoforms. Protein and mRNA levels of CYP1A1 and CYP1A2 along with CYP1A activities were examined in rat liver after a single oral administration of 500 mg/kg TSU-68. CYP1A-mediated ethoxyresorufin O-deethylation and TSU-68 hydroxylation activities reached the maximum at 12 hr. The activities were maintained up to 24 hr and then slowly decreased down to control levels. Protein levels of both CYP1A1 and CYP1A2 were also rapidly induced with temporal profiles similar to the profile of CYP1A activity. In contrast, unlike CYP1A2 mRNA levels, which peaked at 12 hr and almost returned to control levels by 48 hr, CYP1A1 mRNA levels peaked as early as 3 hr and returned to control levels by 24 hr. Thus, CYP1A1 showed more rapid elevation and turnover of its mRNA than CYP1A2. In conclusion, TSU-68 administered to rats rapidly induced mRNA and protein of CYP1A1 and CYP1A2 as well as CYP1A activity. Furthermore, the data showed a difference in the time-dependent induction between CYP1A1 and CYP1A2 mRNAs.

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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)

Cited by 14 publications

References 29 publications

AhR activation underlies the CYP1A autoinduction by A-998679 in rats

AhR activation underlies the CYP1A autoinduction by A-998679 in rats

Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer

Time-dependent Induction of Rat Hepatic CYP1A1 and CYP1A2 Expression after Single-dose Administration of the Anti-angiogenic Agent TSU-68

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