title: Preclinical pharmacokinetic analysis of SNX-2112, a novel Hsp90 inhibitor, in rats.
abstract: SNX-2112 is a novel Hsp90 inhibitor. The aim of this study was to investigate the pharmacokinetics, tissue distribution, plasma protein binding and excretion profiles of SNX-2112 in Sprague-Dawley rats after a single intravenous injection. The pharmacokinetic properties of SNX-2112 were examined after a single i.v. injection of 2.5, 5, and 10mg/kg to rats, respectively. The tissue distribution and urinary, fecal, and biliary excretion patterns of SNX-2112 were investigated following a single i.v. injection of 10mg/kg. The results suggested that the pharmacokinetic properties of SNX-2112 fitted well into a two-compartment open model with t(1/2β) values of 9.96±4.32, 10.43±4.06, 10.41±4.38h and area under the curve values of 7.62±1.03, 8.10±0.77, 15.80±1.00(μg/mL) h according to the single doses of 2.5, 5, and 10mg/kg, respectively. Approximately 0.13±0.09% and 3.62±0.77% of SNX-2112 were excreted via the urine and feces within 72h, respectively; 2.59±0.67% was excreted into the bile up to 24h after a single i.v. injection of 10mg/kg. The major elimination route was therefore through excretion in the feces. The binding rate of SNX-2112 with plasma protein was found to be concentration-dependent. In conclusion, this study first provided the full pharmacokinetic characteristics and tissue distribution of SNX-2112, which would be helpful for its clinical regiment design.
authors.affiliation: Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Q Q
authors.initials: QQ
authors.lastname: Zhai
authors.forename: G Q
authors.initials: GQ
authors.lastname: Gong
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: M
authors.initials: M
authors.lastname: Xia
authors.forename: G W
authors.initials: GW
authors.lastname: Xing
authors.forename: X F
authors.initials: XF
authors.lastname: You
authors.forename: Y F
authors.initials: YF
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112