Abstract
MGCD0103, an isotype-selective histone deacetylase inhibitor (HDACi), has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In order to investigate the effects of MGCD0103 on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of human CYP2B1, CYP1A2, CYP2C11, CYP2D6, CYP3A4, and CYP2C9. The rats were randomly divided into MGCD0103 group (Low, Medium, and High) and control group. The MGCD0103 group rats were given 20, 40, and 80 mg/kg (Low, Medium, and High) MGCD0103 by continuous intragastric administration for 7 days. Six probe drugs, bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole, were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for tolbutamide in rats were observed by comparing MGCD0103 group with control group. Continuous 7-day intragastric administration of MGCD0103 slightly induces the activities of CYP2C11 of rats.
Highlights
Cytochrome P450 (CYP) enzymes are essential for most biotransformation steps of xenobiotics and endogenous molecules [1, 2]
SAHA and FK-228 are broad-spectrum histone deacetylases (HDACs) inhibitors (HDACI) that have been approved by FDA for the treatment of refractory cutaneous T-cell lymphoma (CTCL) [9, 10]
The intraday and interday accuracy ranged from 90% to 115%
Summary
Cytochrome P450 (CYP) enzymes are essential for most biotransformation steps of xenobiotics and endogenous molecules [1, 2]. Undesirable drug-drug interactions have been reported when HDACI is coadministrated with other anticancer agents [14, 15]. Exploring the influence on CYP enzyme caused by MGCD0103 would facilitate understanding its metabolic behavior and avoid some undesirable drug-drug interactions or toxicity. No study on the effects of MGCD0103 on the metabolic capacity of CYP enzyme was reported. In this study, six probe drugs were employed to evaluate effect of MGCD0103 on the metabolic capacity of human CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. The effects of MGCD0103 on rat CYP enzyme activity will be evaluated according to the changes in the pharmacokinetic parameters of six specific probe drugs
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