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

被引:29
作者
Berg, SL [1 ]
Stone, J
Xiao, JJ
Chan, KK
Nuchtern, J
Dauser, R
McGuffey, L
Thompson, P
Blaney, SM
机构
[1] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA
[2] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA
[3] Ohio State Univ, Coll Med, Columbus, OH 43210 USA
[4] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA
[5] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA
[6] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA
关键词
depsipeptide; FR901228; CSF penetration; pharmacokinetics;
D O I
10.1007/s00280-004-0766-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/m(2) 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 muM.min, and the total body clearance was 350+/-65 ml/min/m(2). 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 (AUC(CSF):AUC(plasma)) 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.
引用
收藏
页码:85 / 88
页数:4
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