In Vitro Phase I Cytochrome P450 Metabolism, Permeability and Pharmacokinetics of SB639, a Novel Histone Deacetylase Inhibitor in Preclinical Species

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 SB6...

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Bibliographic Details
Published in:Biological & Pharmaceutical Bulletin 2007, Vol.30(5), pp.1021-1024
Main Authors: Venkatesh, Pilla Reddy, Goh, Evelyn, Zeng, Peizi, New, Lee Sun, Xin, Liu, Pasha, Mohammed Khalid, Sangthongpitag, Kanda, Yeo, Pauline, Kantharaj, Ethirajulu
Format: Article
Language:eng ; jpn
Subjects:
Administration, Oral
Animals
Benzimidazoles - blood
Benzimidazoles - pharmacokinetics
bioavailability
Biological Availability
Caco-2 Cells
Cell Membrane Permeability - drug effects
Cytochrome P-450 Enzyme System - metabolism
Dogs
Drug Evaluation, Preclinical
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacokinetics
Female
Half-Life
histone deacetylase (HDAC)
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids - blood
Hydroxamic Acids - pharmacokinetics
Male
Metabolic Detoxication, Phase I
Mice
Mice, Inbred BALB C
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Microsomes, Liver - metabolism
mouse
pharmacokinetics
Pyrroles - blood
Pyrroles - pharmacokinetics
Pyrrolidines
Rats
Rats, Wistar
SB639
suberoylanilide hydroxamic acid (SAHA)
Vorinostat
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Summary: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.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.30.1021