Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993).
Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993).
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DOI：
10.1007/s00280-014-2447-3
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发表时间：
2014-06
影响因子：
3
通讯作者：
Ames, Matthew M.
中科院分区：
文献类型：
--
作者：
Reid, Joel M.;Buhrow, Sarah A.;Gilbert, Judith A.;Jia, Lee;Shoji, Mamoru;Snyder, James P.;Ames, Matthew M.
Curcumin, a keto-enol constituent of turmeric, has in vitro and in vivo antitumor activity. However, in vivo potency is low due to poor oral absorption. The mono-carbonyl analog, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone acetate (EF-24, NSC 716993), exhibited broad spectrum activity in the NCI anti-cancer cell line screen and potent anti-angiogenesis activity in a HUVEC cell migration assay. The purpose of this study was to characterize the preclinical pharmacology of EF-24 in mice. EF-24 plasma stability, protein binding, pharmacokinetics and metabolism were characterized utilizing an LC/MS/MS assay. An LC/MS/MS assay that incorporated protein precipitation with methanol, reverse-phase HPLC separation under gradient elution using an aqueous methanol mobile phase containing 0.1% formic acid and positive electrospray ionization detection of the m/z 312 > 149 transition for EF-24. The assay was linear over the range 7.8-1000 nM. Plasma protein binding was > 98% with preferential binding to albumin. EF-24 plasma disposition in mice after i.v. administration of a 10 mg/kg dose was best fit to a 3-compartment open model. The terminal elimination half-life and plasma clearance values were 73.6 min and 0.482 L/min/kg, respectively. EF-24 bioavailability was 60% and 35% after oral and i.p. administration, respectively. NADPH-dependent metabolism of EF-24 loss in liver microsomal preparations yielded several metabolites consistent with EF-24 hydroxylation and reduction.
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影响因子：
5.6
作者：
Olivera A;Moore TW;Hu F;Brown AP;Sun A;Liotta DC;Snyder JP;Yoon Y;Shim H;Marcus AI;Miller AH;Pace TW
通讯作者：
Pace TW
影响因子：
2.3
作者：
Adams, BK;Cai, JY;Shoji, M
通讯作者：
Shoji, M
影响因子：
3.5
作者：
Adams, BK;Ferstl, EM;Shoji, M
通讯作者：
Shoji, M
影响因子：
3.6
作者：
Kasinski, Andrea L.;Du, Yuhong;Fu, Haian
通讯作者：
Fu, Haian
影响因子：
37.3
作者：
Landais I;Hiddingh S;McCarroll M;Yang C;Sun A;Turker MS;Snyder JP;Hoatlin ME
通讯作者：
Hoatlin ME