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

Biopharm Drug Dispos. 2005 Jan;26(1):13-20. doi: 10.1002/bdd.423.


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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Brain / drug effects
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Flumazenil / antagonists & inhibitors
  • Flumazenil / pharmacology
  • Fluorobenzenes / administration & dosage
  • Fluorobenzenes / blood
  • Fluorobenzenes / pharmacokinetics*
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Transgenic
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects*
  • Rodentia / metabolism*
  • Species Specificity*
  • Triazoles / administration & dosage
  • Triazoles / blood
  • Triazoles / pharmacokinetics*
  • Tritium


  • Fluorobenzenes
  • Receptors, GABA-A
  • Triazoles
  • Tritium
  • Flumazenil
  • L 838,417