title: In vitro phase I cytochrome P450 metabolism, permeability and pharmacokinetics of SB639, a novel histone deacetylase inhibitor in preclinical species.
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 microM. 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.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, S*BIO Pte Ltd, Singapore.
authors.forename: Pilla Reddy
authors.initials: PR
authors.lastname: Venkatesh
authors.forename: Evelyn
authors.initials: E
authors.lastname: Goh
authors.forename: Peizi
authors.initials: P
authors.lastname: Zeng
authors.forename: Lee Sun
authors.initials: LS
authors.lastname: New
authors.forename: Liu
authors.initials: L
authors.lastname: Xin
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Ethirajulu
authors.initials: E
authors.lastname: Kantharaj
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D050216:Metabolic Detoxication, Phase I; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics*; D011759:Pyrrolidines; D051381:Rats; D017208:Rats, Wistar; D000077337:Vorinostat
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C520686:N-hydroxy-3-(2-phenethyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazol-5-yl)acrylamide; D011758:Pyrroles; D011759:Pyrrolidines; D000077337:Vorinostat; D003577:Cytochrome P-450 Enzyme System