title: Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L-838417.
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 (<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 [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/ml g, respectively) and mice (63 ng/ml and 53 ng/ml g, 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.
authors.affiliation: Merck Sharp and Dohme, Department of Medicinal Chemistry (Drug Metabolism and Pharmacokinetics Section), Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. paul_scottstevens@merck.com
authors.forename: P
authors.initials: P
authors.lastname: Scott-Stevens
authors.forename: J R
authors.initials: JR
authors.lastname: Atack
authors.forename: B
authors.initials: B
authors.lastname: Sohal
authors.forename: P
authors.initials: P
authors.lastname: Worboys
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005442:Flumazenil / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012377:Rodentia / Q000378:metabolism*; D013045:Species Specificity; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014316:Tritium
chemical_list: D005464:Fluorobenzenes; D011963:Receptors, GABA-A; D014230:Triazoles; D014316:Tritium; D005442:Flumazenil; C409903:L 838,417