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The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method.

Cai J, Zhang Q, Lin K, Hu L, Zheng Y - Biomed Res Int (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325000, China.

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.

No MeSH data available.


Related in: MedlinePlus

The pharmacokinetic profiles of bupropion (a), omeprazole (b), phenacetin (c), testosterone (d), tolbutamide (e), and metoprolol (f) in control group and MGCD0103 group (low, medium, and high) rats (n = 10). From the result, no difference in pharmacokinetic behaviors can be observed between low, medium dosage group and control group. On the other hand, no significant difference for AUC, t1/2 of omeprazole, phenacetin, metoprolol, testosterone, and bupropion (p > 0.05) between the high dosage group and control group was observed. However, the pharmacokinetic parameters of tolbutamide experienced obvious change with decreased AUC(0–t) (p < 0.05) and increased CL (p < 0.05) after the dosage increase.
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fig1: The pharmacokinetic profiles of bupropion (a), omeprazole (b), phenacetin (c), testosterone (d), tolbutamide (e), and metoprolol (f) in control group and MGCD0103 group (low, medium, and high) rats (n = 10). From the result, no difference in pharmacokinetic behaviors can be observed between low, medium dosage group and control group. On the other hand, no significant difference for AUC, t1/2 of omeprazole, phenacetin, metoprolol, testosterone, and bupropion (p > 0.05) between the high dosage group and control group was observed. However, the pharmacokinetic parameters of tolbutamide experienced obvious change with decreased AUC(0–t) (p < 0.05) and increased CL (p < 0.05) after the dosage increase.

Mentions: The main pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole calculated from noncompartment model analysis were summarized in Tables 1, 2, and 3. The representative profiles of concentration of drugs (phenacetin, metoprolol, testosterone, omeprazole, tolbutamide, and bupropion) versus time were presented in Figure 1.


The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method.

Cai J, Zhang Q, Lin K, Hu L, Zheng Y - Biomed Res Int (2015)

The pharmacokinetic profiles of bupropion (a), omeprazole (b), phenacetin (c), testosterone (d), tolbutamide (e), and metoprolol (f) in control group and MGCD0103 group (low, medium, and high) rats (n = 10). From the result, no difference in pharmacokinetic behaviors can be observed between low, medium dosage group and control group. On the other hand, no significant difference for AUC, t1/2 of omeprazole, phenacetin, metoprolol, testosterone, and bupropion (p > 0.05) between the high dosage group and control group was observed. However, the pharmacokinetic parameters of tolbutamide experienced obvious change with decreased AUC(0–t) (p < 0.05) and increased CL (p < 0.05) after the dosage increase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556830&req=5

fig1: The pharmacokinetic profiles of bupropion (a), omeprazole (b), phenacetin (c), testosterone (d), tolbutamide (e), and metoprolol (f) in control group and MGCD0103 group (low, medium, and high) rats (n = 10). From the result, no difference in pharmacokinetic behaviors can be observed between low, medium dosage group and control group. On the other hand, no significant difference for AUC, t1/2 of omeprazole, phenacetin, metoprolol, testosterone, and bupropion (p > 0.05) between the high dosage group and control group was observed. However, the pharmacokinetic parameters of tolbutamide experienced obvious change with decreased AUC(0–t) (p < 0.05) and increased CL (p < 0.05) after the dosage increase.
Mentions: The main pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole calculated from noncompartment model analysis were summarized in Tables 1, 2, and 3. The representative profiles of concentration of drugs (phenacetin, metoprolol, testosterone, omeprazole, tolbutamide, and bupropion) versus time were presented in Figure 1.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325000, China.

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.

No MeSH data available.


Related in: MedlinePlus