Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L‐838417

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Abstract
The pharmacokinetics of L‐838417, a GABAA receptor subtype selective benzodiazepine site agonist, were studied in rats and mice after single oral (p.o.), intraperitoneal (i.p.) and intravenous (i.v.) doses. In both species L‐838417 was well absorbed following i.p. administration and whilst in rats p.o. bioavailability was good (41%), in mice it was negligible (3H]Ro 15‐1788 in vivo binding assay. Although the resulting dose‐occupancy relationship for both species demonstrated a dose‐dependent increase in receptor occupancy, appreciable variability was observed at low dose levels, potentially making interpretation of behavioural responses difficult. In contrast, a clear relationship between plasma and brain concentrations and receptor occupancy were determined suggesting the observed dose‐occupancy variability is a consequence of the pharmacokinetic properties of L‐838417. The plasma and brain concentrations required to occupy 50% of the benzodiazepine binding sites were similar in both rats (28 ng/ml and 33 ng/mlg, respectively) and mice (63 ng/ml and 53 ng/mlg, respectively), with a non‐linear concentration response observed with increasing doses of L‐838417. These studies demonstrate the importance of utilizing pharmacokinetic/receptor occupancy data when interpreting pharmacodynamic responses at a given dose. Copyright © 2004 John Wiley & Sons, Ltd.