ANTAGONISM OF SEROTONIN(3) (5-HT3) RECEPTORS WITHIN THE BLOOD-BRAIN-BARRIER PREVENTS CISPLATIN-INDUCED EMESIS IN DOGS

Recently discovered serotonin, (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site whe re 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antieme tic 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-Q UAT were used in this study. Zatosetron and zatosetron-QUAT showed hig h affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats w ith an approximate ID50 of 0.7 and 0.2 mu g/kg i.v., respectively. Zat osetron and tropisetron significantly inhibited cisplatin-evoked emesi s in dogs (estimated ID50 values of 34.4 +/- 2.3 mu g/kg and 108.3 +/- 4.8 mu g/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v. ) had no effect. [C-14]-zatosetron-QUAT (100 mu g/kg) was not detected in the brain after i.v. administration to rats, consistent with the i nability of charged compounds to achieve significant brain concentrati ons. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT red uced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). The se studies suggest that, in dogs, antagonism of 5-HT3 receptors locate d within the blood-brain barrier is important to block cisplatin-induc ed emesis.