Received for publication August 22, 2005.
Revised January 31, 2006.
Accepted for publication January 31, 2006.

Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABA_A 5-selective compound L-655,708

Abstract

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 hr) and selective occupancy of 5-containing GABA_A receptors suitable for behavioural 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. This plasma concentration was therefore chosen as a target to achieve relatively selective occupancy of 5-containing receptors using subcutaneous 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 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 hr 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.

Key words: CNS pharmacokinetics, drug development, drug discovery, pharmacokinetic/pharmacodynamic modeling, pharmacokinetics