Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer

  • Authors:
    • Jun Yang
    • Sunjoo Ahn
    • Zengru Wu
    • Dong-Jin Hwang
    • Duane D. Miller
    • James T. Dalton
  • View Affiliations

  • Published online on: April 20, 2012     https://doi.org/10.3892/ijo.2012.1442
  • Pages: 337-344
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Abstract

The objective of these studies was to examine the murine pharmacokinetics, pharmacodynamics and metabolism of (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (Indole 15), a novel tubulin inhibitor for the treatment of cancer. We developed HPLC and LC/MS/MS assays to quantitate Indole 15 and characterize its metabolites in vivo. Pharmacokinetic studies were performed after intravenous (IV), oral (PO) and subcutaneous (SC) administration of 10 mg/kg doses to male ICR mice. Urine and fecal samples were also collected over a 72-h period to identify metabolites. Pharmacodynamic studies were conducted by monitoring the tumor size change during a period of two weeks in PC-3 tumor bearing mice after daily IV administration of Indole 15 at doses of 0, 10, 50, 100 and 150 mg/kg. The pooled plasma concentration data after administration via different dose routes was simultaneously fitted by a two-compartmental model. Indole 15 was moderately well absorbed after PO and SC administration, with a bioavailable fraction of 0.27 and 0.72, respectively. The steady state volume distribution (Vss) and clearance (CL) were estimated to be 7.0 l/kg and 4.36 l/h/kg, respectively. The mean data of PC-3 tumor growth in mice was fitted well by a transduction model using fixed plasma pharmacokinetics as a driving function. Analysis of the metabolites in mice indicated that the compound undergoes extensive oxidative metabolism with subsequent sulfation. These studies demonstrate that favorable pharmacokinetic and pharmacodynamic properties of Indole 15 offer hope for achieving pharmacological activity in early clinical trials.

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July 2012
Volume 41 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Yang J, Ahn S, Wu Z, Hwang D, Miller DD and Dalton JT: Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer. Int J Oncol 41: 337-344, 2012.
APA
Yang, J., Ahn, S., Wu, Z., Hwang, D., Miller, D.D., & Dalton, J.T. (2012). Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer. International Journal of Oncology, 41, 337-344. https://doi.org/10.3892/ijo.2012.1442
MLA
Yang, J., Ahn, S., Wu, Z., Hwang, D., Miller, D. D., Dalton, J. T."Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer". International Journal of Oncology 41.1 (2012): 337-344.
Chicago
Yang, J., Ahn, S., Wu, Z., Hwang, D., Miller, D. D., Dalton, J. T."Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer". International Journal of Oncology 41, no. 1 (2012): 337-344. https://doi.org/10.3892/ijo.2012.1442