Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 5, pp 1301–1306

Pharmacokinetics and tissue and tumor exposure of CP-31398, a p53-stabilizing agent, in rats

  • Izet M. Kapetanovic
  • Miguel Muzzio
  • David L. McCormick
  • Thomas N. Thompson
  • William D. Johnson
  • Thomas L. Horn
  • Altaf Mohammed
  • Chinthalapally V. Rao
  • Levy Kopelovich
Original Article

DOI: 10.1007/s00280-011-1811-9

Cite this article as:
Kapetanovic, I.M., Muzzio, M., McCormick, D.L. et al. Cancer Chemother Pharmacol (2012) 69: 1301. doi:10.1007/s00280-011-1811-9

Abstract

Purpose

CP-31398 (N′-[2-[(E)-2-(4-methoxyphenyl)ethenyl]quinazolin-4-yl]-N,N-dimethylpropane-1,3-diamine hydrochloride) is one of the new class of agents that can stabilize the DNA-binding domain of p53 and thereby maintain the activity of p53 as a tumor suppressor and transcription factor. Through its activity as a p53 stabilizer, CP-31398 demonstrates significant cancer preventive and therapeutic activity in several in vivo animal models. The objective of the current study was to describe the pharmacokinetic profile and tissue distribution of this novel agent following intravenous or oral (gavage and dietary) administration.

Methods

CP-31398 was administered to male CD and F344 rats as a single intravenous bolus dose or by daily oral gavage dosing. Male F344 rats also received drug as an ad libitum dietary supplement. Plasma, liver, skin, colon, and colon tumor samples were collected after oral dosing. Concentrations of CP-31398 in plasma and tissue samples were analyzed using LC–MS/MS, and the resultant data were subjected to a non-compartmental pharmacokinetic analysis.

Results

Bioavailability (12–32%), elimination half-life (14–20 h), clearance (4.2–4.8 l/h/kg), and volume of distribution (70–82 l/kg) were determined. Tissue levels of CP-31398 after oral (gavage or diet) administration were several orders of magnitude higher than were corresponding plasma concentrations; CP-31398 levels were especially high in colon and liver. Levels of CP-31398 in tissues were higher after gavage dosing than after dietary administration.

Conclusions

CP-31398 is bioavailable and has a relatively long elimination half-life, which supports the achievement of plasma steady-state levels with a once daily dosing regimen. CP-31398 exhibits a dramatically high volume of distribution, which is consistent with its tissue concentrations being much higher than corresponding plasma levels. It is accumulated in colon tumor tissues, albeit at lower concentrations than found in liver, skin, and colon.

Keywords

p53 Chemoprevention Pharmacokinetics Liver Colon tumor Rat 

Copyright information

© Springer-Verlag (outside the USA) 2012

Authors and Affiliations

  • Izet M. Kapetanovic
    • 1
  • Miguel Muzzio
    • 2
  • David L. McCormick
    • 2
  • Thomas N. Thompson
    • 3
  • William D. Johnson
    • 2
  • Thomas L. Horn
    • 2
  • Altaf Mohammed
    • 4
  • Chinthalapally V. Rao
    • 4
  • Levy Kopelovich
    • 1
  1. 1.Chemopreventive Agent Development Research Group, Division of Cancer PreventionNational Cancer InstituteBethesdaUSA
  2. 2.Life Sciences GroupIIT Research InstituteChicagoUSA
  3. 3.R&D Services Pharma ConsultingOmahaUSA
  4. 4.Center for Chemoprevention and Drug DevelopmentThe University of Oklahoma Health Sciences CenterOklahoma CityUSA

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