title: Antagonism of serotonin3 (5-HT3) receptors within the blood-brain barrier prevents cisplatin-induced emesis in dogs.
abstract: Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gidda
authors.forename: D C
authors.initials: DC
authors.lastname: Evans
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: C J
authors.initials: CJ
authors.lastname: Parli
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001665:Binding Sites; D001812:Blood-Brain Barrier; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D004285:Dogs; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C064877:zatosetron; D002945:Cisplatin