In Vitro Phase I Cytochrome P450 Metabolism, Permeability and Pharmacokinetics of SB639, a Novel Histone Deacetylase Inhibitor in Preclinical Species
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- Venkatesh Pilla Reddy
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Goh Evelyn
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Zeng Peizi
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- New Lee Sun
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Xin Liu
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Pasha Mohammed Khalid
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Sangthongpitag Kanda
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Yeo Pauline
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
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- Kantharaj Ethirajulu
- Department of Pharmacokinetics and Drug Metabolism, S<sup>*</sup>BIO Pte Ltd.
Bibliographic Information
- Other Title
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- In vitro phase 1 cytochrome P450 metabolism, permeability and pharmacokinetics of SB639, a novel histone deacetylase inhibitor in preclinical species
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Abstract
In vitro liver microsomal stability, permeability, pharmacokinetics (PK) and oral bioavailability of SB639, a novel HDACi (Histone Deacetylase inhibitor), were determined. The in vitro metabolism was examined in mouse, rat, dog and human liver microsomes. The permeability and efflux potential of SB639 were determined using Caco-2 cell monolayers. To determine pharmacokinetics and oral bioavailability, blood samples were drawn at pre-determined intervals up to 24 h post-dose after single intravenous (i.v.) or oral (p.o.) administration of SB639 to mouse or rat. The concentrations of SB639 in plasma samples were determined by a validated LC-MS/MS method. In vitro liver microsomal stability data revealed that SB639 was stable in human and dog liver microsomes, unstable in mouse and rat liver microsomes. The Caco-2 data has shown that SB639 is highly permeable with an apparent permeability of 3.01·10−6 cm/s at 10 μM. After oral administration, maximum concentrations of SB639 were achieved within 0.5 h of post dose. Following i.v. administration, the concentration of SB639 declined in a bi-exponential fashion with terminal elimination half-life of 1.67 h for mice and 1.12 h for rats. The systemic clearance and volume of distribution of SB639 in mice were 15.8 l/h/kg and 38 l/kg, respectively, while the respective values in rats were 3.84 l/h/kg and 3.67 l/kg. Elimination half-life in rats ranged between 1.12—2.26 h. Absolute oral bioavailability of SB639 in mouse and rat was 13% and 10%, respectively. In conclusion, the superior potency, physicochemical and PK properties of SB639 compared to the recently FDA approved drug Zolinza (Suberoylanilide hydroxamic acid or Vorinostat) in the preclinical setting makes it a potential clinical candidate.
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 30 (5), 1021-1024, 2007
The Pharmaceutical Society of Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390282679603759104
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- NII Article ID
- 110006273311
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- NII Book ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- NDL BIB ID
- 8714662
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed