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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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Abstract

Purpose

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 anticancer cell line screen and potent antiangiogenesis activity in a HUVEC cell migration assay. The purpose of this study was to characterize the preclinical pharmacology of EF-24 in mice.

Methods

EF-24 plasma stability, protein binding, pharmacokinetics, and metabolism were characterized utilizing an LC/MS/MS assay.

Results

An LC/MS/MS assay 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 7.8–1,000 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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Acknowledgments

MS and JPS are grateful to Dennis Liotta (Emory University) for generous support of preparation of the curcumin analogs. This study was supported by National Cancer Institute Contract N01-CM-07105, US Department of Defense, Division of US Army DAMD17-00-1-0241 (MS and JPS), BC074220 (MS and JPS) and National Cancer Institute 5 R21 CA139035-2 (MS and JPS).

Conflict of interest

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Authors and Affiliations

  1. Department of Oncology, Division of Oncology Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Joel M. Reid, Sarah A. Buhrow, Judith A. Gilbert & Matthew M. Ames

  2. Toxicology and Pharmacology Branch, Developmental Therapeutics Program, DCTD, NCI, Rockville, MD, 20852, USA

    Lee Jia

  3. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA

    Mamoru Shoji

  4. Department of Chemistry and Emory Institute for Drug Development, Emory University, 1515 Dickey Drive, Atlanta, GA, 30322, USA

    James P. Snyder

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  1. Joel M. Reid
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  2. Sarah A. Buhrow
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  3. Judith A. Gilbert
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  4. Lee Jia
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  5. Mamoru Shoji
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  6. James P. Snyder
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  7. Matthew M. Ames
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Correspondence to Joel M. Reid.

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Reid, J.M., Buhrow, S.A., Gilbert, J.A. et al. Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993). Cancer Chemother Pharmacol 73, 1137–1146 (2014). https://doi.org/10.1007/s00280-014-2447-3

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  • DOI: https://doi.org/10.1007/s00280-014-2447-3

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