title: Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA alpha5-selective compound L-655,708.
abstract: The pharmacokinetic and pharmacodynamic (i.e., receptor occupancy) properties of L-655,708, a compound with selectivity for alpha5-over alpha1-, alpha2-, and alpha3-containing GABA(A) receptors, were examined in rats with the aim of developing a formulation that would give sustained (up to 6 h) and selective occupancy of alpha5-containing GABA(A) receptors suitable for behavioral studies. Standard rat pharmacokinetic analyses showed that L-655,708 has a relatively short half-life with kinetics in the brain mirroring those in the plasma. In vivo binding experiments showed that plasma concentrations of around 100 ng/ml gave relatively selective in vivo occupancy of rat brain alpha5-versus alpha1-, alpha2-, and alpha3-containing GABA(A) receptors. Therefore, this plasma concentration was chosen as a target to achieve relatively selective occupancy of alpha5-containing receptors using s.c. implantations of L-655,708 (0.4, 1.5, or 2.0 mg) formulated into tablets of various size (20 or 60 mg) containing different amounts of L-655,708 and combinations of low and high viscosity hydroxypropyl methylcellulose (LV- and HV-HPMC). The optimum formulation, 1.5 mg of L-655,708 compressed into a 60-mg tablet with 100% HV-HPMC, resulted in relatively constant plasma concentrations being maintained for at least 6 h with very little difference between C(max) concentrations (125-150 ng/ml) and plateau concentrations (100-125 ng/ml). In vivo binding experiments confirmed the selective occupancy of rat brain alpha5-over alpha1-, alpha2-, and alpha3-containing GABA(A) receptors.
authors.affiliation: Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Eastwick Road, Harlow, Essex CM20 2QR, England. john_r_atack@yahoo.co.uk
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Andy
authors.initials: A
authors.lastname: Pike
authors.forename: Ashley
authors.initials: A
authors.lastname: Clarke
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D018756:GABA Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D018756:GABA Antagonists; C511535:Gabra5 protein, rat; D007093:Imidazoles; C105490:L 655,708; D011963:Receptors, GABA-A; D013607:Tablets