title: Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.
abstract: AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Xie
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Jones
authors.affiliation: Sanofi-Aventis, Malvern, Pennsylvania, USA.
authors.forename: Xiaohui Tracey
authors.initials: XT
authors.lastname: Wei
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Coss
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA.|Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA.|College of Medicine, The Ohio State University, Columbus, Ohio, USA.|Gehr Family Center For Leukemia Research Hematologist Malignancies Institute City of Hope, Duarte, CA, 90010, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA.|College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.affiliation: The National Cancer Institute, Rockville, Maryland, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA. phelps.32@osu.edu.|Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA. phelps.32@osu.edu.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, Ohio, 43210, USA. chan.56@osu.edu.|Comprehensive Cancer, The Ohio State University, Columbus, Ohio, USA. chan.56@osu.edu.|The National Cancer Institute, Rockville, Maryland, USA. chan.56@osu.edu.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics*; D051379:Mice; D010654:Phenylbutyrates / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates
keywords: AR-42; histone deacetylase inhibitor; mouse; pharmacokinetics; rat