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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor
Milin R Acharya1, Alex Sparreboom, Edward A Sausville
1Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD 20892, USA.
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.
Insights
MS-275, an anticancer drug, shows low protein binding in humans, with minimal changes due to other drugs. This binding behavior differs significantly across animal species, potentially explaining pharmacokinetic variations.
Area of Science:
- Pharmacology
- Drug Development
- Oncology
Background:
- MS-275 is a histone deacetylase inhibitor investigated as an anticancer therapeutic.
- Understanding protein binding is crucial for predicting drug pharmacokinetics and efficacy.
Purpose of the Study:
- To investigate the role of protein binding in determining the pharmacokinetic behavior of MS-275.
- To quantify the unbound fraction of MS-275 in human and animal plasma.
Main Methods:
- In vitro equilibrium dialysis using [G-(3)H]MS-275 and 96-well microdialysis plates.
- Ex vivo analysis in five cancer patients receiving oral MS-275 (10 mg/m(2)).
- Assessment of drug-drug interactions and species-specific protein binding.
Main Results:
- The mean unbound fraction (f(u)) of MS-275 in healthy human plasma was 0.188 ± 0.0075, and 0.168 ± 0.0144 in cancer patients.
- Binding was concentration-independent, indicating low affinity, and occurred primarily with plasma, followed by alpha(1)-acid glycoprotein and albumin.
- Ibuprofen and metoclopramide caused slight increases in f(u), suggesting weak competitive displacement. Human f(u) was significantly lower than in mouse, rat, rabbit, dog, and pig plasma.
Conclusions:
- MS-275 exhibits low, non-specific protein binding in humans.
- Species-dependent differences in MS-275 protein binding may contribute to observed pharmacokinetic variations.
- Further studies are warranted to fully elucidate the clinical implications of MS-275's protein binding profile.
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