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

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/m(2). The dialysis method uses a tracer amount of [G-(3)H]MS-275 on a 96-well microdialysis plate with a 5-kDa cut-off membrane, and requires 250 microl sample. The time to equilibrium was established to be within 5 h, and the mean unbound fraction of MS-275 (f (u)) 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 > alpha(1)-acid glycoprotein > albumin. Among 19 tested drugs, a slightly increased f (u) was observed in the presence of only ibuprofen (f (u), 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, f (u) 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.