Action of the racemate and the isomers of the platelet-activating factor antagonist bepafant (WEB 2170) after oral administration to guinea-pigs and rats.
The aim of the present study was to clarify whether there is a difference in terms of potency and pharmacodynamic half time between the isomers and the racemate of the platelet-activating factor antagonist WEB 2170 (bepafant) after oral administration to guinea-pigs or rats. The following experiments were performed in the guinea-pig. Infusion of platelet-activating factor at 30 ng/(kg x min) for 30 min to anaesthetized guinea-pigs induced a decrease of respiratory flow and mean arterial blood pressure. Oral pretreatment with WEB 2170 or isomers, respectively, 60 min before infusion of platelet-activating factor inhibited these changes in a dose-dependent manner. The ED50s for inhibition of respiratory flow were: (-) WEB 2170 = 0.018 (0.009-0.036) mg/kg p.o; (+/-) WEB 2170 = 0.021 (0.015-0.03) mg/kg p.o.; (+) WEB 2170 = 1.55 (1.01-3.05) mg/kg p.o. Similar ED50 values were obtained for inhibition of decrease of MAP. Doses of isomers and racemate of WEB 2170 that provided almost complete protection against platelet-activating factor at 1 h after administration were chosen for determination of the duration of the protective effect after oral administration. Oral (-) WEB 2170 or (+/-) WEB 2170 showed almost identical time-response curves for inhibition (t1/2 = 14-17 h; 0.1 mg/kg p.o.) in the guinea-pig, whereas the duration of action of (+) WEB 2170 (3-6 h; 8 mg/kg) was significantly shorter. The following experiments were conducted in the rat. Oral pretreatment with WEB 2170 racemate and isomers resulted in a dose-dependent reversal of platelet-activating factor-induced hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
Heuer
H O
HO
Department of Pharmacology, Boehringer Ingelheim KG, Federal Republic of Germany.
Keller
B
B
Urich
K
K
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D012123:Pulmonary Ventilation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C063964:bepafant