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Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates

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Abstract

Purpose

Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration.

Design

Depsipeptide was administered intravenously at a dose of 10 mg/m2 over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods.

Results

The peak plasma concentration (median±SD) was 245±50 nM and occurred within the first 2 h of the infusion. The terminal half-life was 205±315 min, the AUC extrapolated to infinity was 50±15 μM·min, and the total body clearance was 350±65 ml/min/m2. In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 nM in one animal and 2.3 nM in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUCCSF:AUCplasma) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae.

Conclusions

Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC50 of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

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Authors and Affiliations

  1. Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

    Stacey L. Berg, Jeffery Stone, Leticia McGuffey, Patrick Thompson & Susan M. Blaney

  2. College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA

    Jim J. Xiao

  3. Colleges of Pharmacy and Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA

    Kenneth K. Chan

  4. Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA

    Jed Nuchtern

  5. Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA

    Robert Dauser

  6. Texas Children’s Cancer Center, 6621 Fannin Street, CC1410.00, Houston, TX 77030, USA

    Stacey L. Berg

Authors
  1. Stacey L. Berg
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  2. Jeffery Stone
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  3. Jim J. Xiao
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  4. Kenneth K. Chan
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  5. Jed Nuchtern
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  6. Robert Dauser
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  7. Leticia McGuffey
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  8. Patrick Thompson
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  9. Susan M. Blaney
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Correspondence to Stacey L. Berg.

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Berg, S.L., Stone, J., Xiao, J.J. et al. Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother Pharmacol 54, 85–88 (2004). https://doi.org/10.1007/s00280-004-0766-5

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  • DOI: https://doi.org/10.1007/s00280-004-0766-5

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