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RAT PHARMACOKINETICS AND PHARMACODYNAMICS OF A SUSTAINED RELEASE FORMULATION OF THE GABA_A 5-SELECTIVE COMPOUND L-655,708

Departments of in Vivo Neuroscience (J.R.A., S.M.C., R.M.M., G.R.D.) and Drug Metabolism and Pharmacokinetics (A.P., B.S.), Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom; and Devlab, Merck Sharp & Dohme Research Laboratories, Hoddesdon, Hertfordshire, United Kingdom (A.C.)

The pharmacokinetic and pharmacodynamic (i.e., receptor occupancy) properties of L-655,708, a compound with selectivity for 5-over 1-, 2-, and 3-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 5-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 5-versus 1-, 2-, and 3-containing GABA_A receptors. Therefore, this plasma concentration was chosen as a target to achieve relatively selective occupancy of 5-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 5-over 1-, 2-, and 3-containing GABA_A receptors.