title: Physiologically based pharmacokinetic modeling of SNU-0039, an anti-Alzheimer's agent, in rats.
abstract: The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of β-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K(p)) for SNU-0039 in rats ranged from a low of 0.779 ± 0.314 (muscle) to a high of 5.71 ± 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Yoon-Jee
authors.initials: YJ
authors.lastname: Chae
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C570118:2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl)benzofuran; D001572:Benzofurans; D018697:Nootropic Agents