title: Pharmacokinetics and brain uptake of AM-36, a novel neuroprotective agent, following intravenous administration to rats.
abstract: The plasma pharmacokinetics and brain uptake of the novel neuroprotective agent AM-36 (1-(2-(4-chlorophenyl)-2-hydroxy)ethyl-4-(3,5-bis-(1,1dimethylethyl)-4-hydroxyphenyl) methylpiperazine) were assessed over 72 h following i.v. administration to male Sprague-Dawley rats. At nominal i.v. doses of 0.2, 1 and 3mg kg(-1), AM-36 exhibited an extremely large volume of distribution (18.2-24.6 L kg(-1)) and a long terminal elimination half-life, ranging from 25.2 to 37.7 h. Over this dose range, AM-36 exhibited linear pharmacokinetics, with no apparent change in clearance, volume of distribution or dose-normalised area under the plasma concentration - time curve. AM-36 was very highly bound to plasma proteins (> 99.6%); however, this did not appear to affect the ability of AM-36 to permeate the blood-brain barrier. Following a single i.v. dose of AM-36 at 3mg kg(-1) to rats, brain concentrations were detected for up to 72 h, and the brain-to-plasma ratios were high at all time points (ranging from 8.2 at 5 min post-dose to 0.9 at 72 h post-dose). The very high brain uptake of AM-36 supports previous in-vivo efficacy studies demonstrating the neuroprotective effects of this compound when administered to rats with middle cerebral artery occlusion.
authors.affiliation: Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Nicolazzo
authors.forename: Tien T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Steuten
authors.forename: Gregg
authors.initials: G
authors.lastname: Smith
authors.forename: Bevyn
authors.initials: B
authors.lastname: Jarrott
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Callaway
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D018696:Neuroprotective Agents; D010879:Piperazines; C401121:AM 36