title: 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.
authors: Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Milin R
authors: MR
authors: Acharya
authors: Alex
authors: A
authors: Sparreboom
authors: Edward A
authors: EA
authors: Sausville
authors: Barbara A
authors: BA
authors: Conley
authors: James H
authors: JH
authors: Doroshow
authors: Jurgen
authors: J
authors: Venitz
authors: William D
authors: WD
authors: Figg
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism*; D004285:Dogs; D006023:Glycoproteins / Q000378:metabolism; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008787:Metoclopramide / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000097:blood / Q000378:metabolism; D009961:Orosomucoid; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013045:Species Specificity; D013552:Swine; D013997:Time Factors
chemical_list: D001549:Benzamides; D001798:Blood Proteins; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; C506108:Orm1 protein, rat; D009961:Orosomucoid; D011725:Pyridines; D012709:Serum Albumin; C118739:entinostat; D008787:Metoclopramide; D007052:Ibuprofen