Volunteer models for predicting antiemetic activity of 5‐HT3‐receptor antagonists.

Abstract

1. Selective 5‐HT3‐receptor antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5‐HT3‐receptor antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5‐HT3‐receptor antagonists. 2. The flare response to intradermal 5‐HT is thought to be mediated by excitation of 5‐HT3‐ receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5‐HT3‐ receptor antagonists but data on duration of action are conflicting. 3. Ipecacuanha‐induced emesis is thought to be mediated through both peripheral and central 5‐HT3‐receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5‐HT3‐receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5‐HT3‐receptor antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice. 1994 The British Pharmacological Society