Pharmacokinetics and anticonvulsant effect of a new hypnotic, CL 284,846, in rats.
OBJECTIVE
CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats.


METHODS
CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection.


RESULTS
Both the steady-state volume of distribution (1636 +/- 162 and 1804 +/- 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 +/- 7.1 and 22.2 +/- 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an Emax model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures.


CONCLUSIONS
Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.
Gaudreault
J
J
Faculté de Pharmacie, Université de Montréal, Québec, Canada.
Varin
F
F
Pollack
G M
GM
D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005260:Female; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; C085665:zaleplon; D010433:Pentylenetetrazole