Studies on the emetic and antiemetic properties of zacopride and its enantiomers.
In ferrets, the oral emetic activity of zacopride was compared with its R- and S-enantiomers. Increasing doses of 0.01, 0.1, 1.0, 10.0 and 31.6 mg/kg of zacopride or its 2 enantiomers were each administered at hourly intervals to separate groups of animals until emesis occurred. The emetic (100%) dose for zacopride and its S-enantiomer was 0.11 mg/kg p.o. (cumulative dose). The R-enantiomer at a cumulative dose of 42.71 mg/kg p.o. produced emesis in 25% of the animals. By the i.p. route zacopride and its S-enantiomer were more potent than the R-enantiomer in blocking the emetic activity of 0.1 mg/kg p.o. of zacopride. The involvement of 5-HT3 mechanisms is indicated by a correlation between zacopride and its enantiomers to cause and prevent emesis and their affinity at 5-HT3 binding sites. Further, the putative 5-HT3 agonists, 2-methyserotonin and phenylbiguanide, at 10 mg/kg p.o., produced emesis that was blocked by zacopride (0.1 mg/kg i.p.) or ICS 205-930 (1 mg/kg i.p.). The results suggest that in the ferret the S-enantiomer is predominantly responsible for both the emetic and antiemetic properties of zacopride and that 5-HT3 agonism and antagonism are involved in these actions.
Sancilio
L F
LF
Department of Pharmacology, A.H. Robins Research Laboratories, Richmond, VA 23261-6609.
Pinkus
L M
LM
Jackson
C B
CB
Munson
H R
HR
D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004639:Emetics; D005289:Ferrets; D008297:Male; D013237:Stereoisomerism
D000932:Antiemetics; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004639:Emetics; C055971:zacopride