Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor

Milin R. Acharya, Alex Sparreboom, Edward A. Sausville, Barbara A. Conley, James H. Doroshow, Jurgen Venitz, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

MS-275 (MS-27-275; 3-pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl- carbamate) is a histone deacetylase inhibitor under clinical development as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of MS-275. The distribution of MS-275 in plasma was studied in vitro using equilibrium dialysis and ex vivo in five cancer patients receiving the drug orally at a dose of 10 mg/m2. The dialysis method uses a tracer amount of [G-3H]MS-275 on a 96-well microdialysis plate with a 5-kDa cut-off membrane, and requires 250 μl sample. The time to equilibrium was established to be within 5 h, and the mean unbound fraction of MS-275 (fu) over a presumed therapeutic concentration range in healthy volunteer human plasma was 0.188 ± 0.0075 as compared to 0.168 ± 0.0144 in cancer patients. The binding was concentration-independent, indicating a low affinity, possibly non-specific and non-saturable process. MS-275 was found to bind in decreasing order to plasma > α1-acid glycoprotein > albumin. Among 19 tested drugs, a slightly increased fu was observed in the presence of only ibuprofen (fu, 0.236 ± 0.001) and metoclopramide (f u, 0.270 ± 0.042), suggesting weakly competitive displacement from protein-binding sites (P < 0.01). Compared to humans, fu was significantly higher in plasma from mouse (0.376), rat (0.393), rabbit (0.355), dog (0.436), and pig (0.439) (P < 0.01), which may explain, in part, the species-dependent pharmacokinetic profile of MS-275 observed previously.

Original languageEnglish
Pages (from-to)275-281
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Keywords

  • Equilibrium dialysis
  • Histone deacetylase inhibitor
  • MS-275
  • Protein binding

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