Abstract
Zatosetron is a potent, orally active 5‐HT~3~ receptor antagonist with a long duration of activity in laboratory animals and humans. Several metabolites have been detected in plasma and urine of humans and experimental animals receiving zatosetron. The present study was designed to explore the pharmacological activity of the detected metabolites, 3‐hydroxyzatosetron, 3‐ketozatosetron, and N‐desmethylzatosetron, relative to the parent molecule. These three metabolites had relatively high affinity at 5‐HT~3~ receptors based on in vitro radioligand binding and inhibited serotonin‐induced bradycardia in urethane‐anesthetized rats after intravenous administration. However, these metabolites had lower affinity and were less potent than zatosetron. Of these metabolites, 3‐hydroxyzatosetron (ED~50~ = 4.0 μg/kg iv) was approximately 5‐fold less potent than zatosetron (ED~50~ = 0.8 μg/kg iv) in vivo and had approximately 10‐fold lower affinity at 5‐HT~3~ receptors in vitro relative to zatosetron. N‐desmethylzatosetron and 3‐ketozatosetron were approximately 15‐fold less potent than zatosetron in vivo as 5‐HT~3~ receptor antagonists. With regard to duration of activity in vivo, after intravenous administration, 3‐hydroxyzatosetron and 3‐ketozatosetron blocked 5‐HT~3~ receptors longer than zatosetron, whereas N‐desmethylzatosetron showed a duration of pharmacological activity similar to zatosetron. A fourth metabolite, zatosetron‐N‐oxide can exist in two isomeric forms, with stereoselective N‐oxidation of zatosetron resulting in formation of only one isomer in humans, zatosetron‐β‐N‐oxide. Zatosetron‐β‐N‐oxide had approximately 100‐fold lower 5‐HT~3~ receptor affinity relative to zatosetron and was approximately 150‐fold less active as an antagonist at 5‐HT~3~ receptors in vivo (ED~50~ = 115 μg/kg iv). Thus, although pharmacological activity was observed with all four metabolites, they were all less active in vivo than zatosetron. Therefore, these metabolites would contribute significantly to the activity of zatosetron only if plasma (and tissue) levels greatly exceeded those of zatosetron. © 1993 Wiley‐Liss, Inc.