Limits...
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

Morphological changes of liver in MGCD0103 treated group at low (a), medium (b), high (c) dosage and control group (d) (hematoxylin-eosin staining, ×200). In low dose, liver cells were arranged in funicular along with central veins and became slightly edematous (a). In middle dose, the structure of liver lobule disappeared with extensive fatty changes in the liver cells (b). In high dose, a plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis and some dark blue fragment of nucleus in lobule appeared (c).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556830&req=5

fig2: Morphological changes of liver in MGCD0103 treated group at low (a), medium (b), high (c) dosage and control group (d) (hematoxylin-eosin staining, ×200). In low dose, liver cells were arranged in funicular along with central veins and became slightly edematous (a). In middle dose, the structure of liver lobule disappeared with extensive fatty changes in the liver cells (b). In high dose, a plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis and some dark blue fragment of nucleus in lobule appeared (c).

Mentions: In low dose group (Figure 2(a)), the hepatic lobule, central veins, and portal areas can be recognized at low magnification; liver cells are arranged in funicular along with central veins; the liver cells become slightly edematous. In middle dose group (Figure 2(b)), the structure of liver lobule disappeared at low magnification. The liver cells experienced extensive fatty changes; some of liver cells are pressed extensively; karyopyknosis liver cells with basophilic nucleus and eosinophilic cytoplasm appeared at high magnification. In high dose group (Figure 2(c)), the structure of liver lobule can be recognized at low magnification. A plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis with some dark blue fragment of nucleus in lobule were observed. According to the pathological changes of liver at different dosage of MGCD0103, MGCD0103 is hepatotoxic and its toxicity is dose-dependent.


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)

Morphological changes of liver in MGCD0103 treated group at low (a), medium (b), high (c) dosage and control group (d) (hematoxylin-eosin staining, ×200). In low dose, liver cells were arranged in funicular along with central veins and became slightly edematous (a). In middle dose, the structure of liver lobule disappeared with extensive fatty changes in the liver cells (b). In high dose, a plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis and some dark blue fragment of nucleus in lobule appeared (c).
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Morphological changes of liver in MGCD0103 treated group at low (a), medium (b), high (c) dosage and control group (d) (hematoxylin-eosin staining, ×200). In low dose, liver cells were arranged in funicular along with central veins and became slightly edematous (a). In middle dose, the structure of liver lobule disappeared with extensive fatty changes in the liver cells (b). In high dose, a plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis and some dark blue fragment of nucleus in lobule appeared (c).
Mentions: In low dose group (Figure 2(a)), the hepatic lobule, central veins, and portal areas can be recognized at low magnification; liver cells are arranged in funicular along with central veins; the liver cells become slightly edematous. In middle dose group (Figure 2(b)), the structure of liver lobule disappeared at low magnification. The liver cells experienced extensive fatty changes; some of liver cells are pressed extensively; karyopyknosis liver cells with basophilic nucleus and eosinophilic cytoplasm appeared at high magnification. In high dose group (Figure 2(c)), the structure of liver lobule can be recognized at low magnification. A plenty of liver cells with steatosis and small, atrophy, hyperchromatic karyopyknosis with some dark blue fragment of nucleus in lobule were observed. According to the pathological changes of liver at different dosage of MGCD0103, MGCD0103 is hepatotoxic and its toxicity is dose-dependent.

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