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

The pharmacokinetics of L‐838417, a GABA A 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 (<1%), precluding this as a route of administration for mouse behavioural studies. Despite having a similar volume of distribution (ca 1.4 l/kg) in rats and mice, L‐838417 was cleared at twice liver blood flow in mice (161 ml/min/kg) and moderately cleared in rats (24 ml/min/kg), potentially explaining the poor oral bioavailability in mice. Finally, as a pharmacodynamic readout the benzodiazepine binding site occupancy was determined in rats (0.3–3 mg/kg, p.o.) and mice (1–30 mg/kg, i.p.) using a [ 3 H]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.