ZATOSETRON, A SELECTIVE 5-HT(3)-RECEPTOR ANTAGONIST - PHARMACOLOGICALACTIVITIES OF HUMAN AND ANIMAL METABOLITES

Zatosetron is a potent, orally active 5-HT3 receptor antagonist with a long duration of activity in laboratory animals and humans. Several m etabolites have been detected in plasma and urine of humans and experi mental animals receiving zatosetron. The present study was designed to explore the pharmacological activity of the detected metabolites, 3-h ydroxyzatosetron, 3-ketozatosetron, and N-desmethylzatosetron, relativ e to the parent molecule. These three metabolites had relatively high affinity at 5-HT3 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 (ED50 = 4.0 mug/kg iv) was approximately 5-fold le ss potent than zatosetron (ED50 = 0.8 mug/kg iv) in vivo and had appro ximately 10-fold lower affinity at 5-HT3 receptors in vitro relative t o zatosetron. N-desmethylzatosetron and 3-ketozatosetron were approxim ately 15-fold less potent than zatosetron in vivo as 5-HT3 receptor an tagonists. With regard to duration of activity in vivo, after intraven ous administration, 3-hydroxyzatosetron and 3-ketozatosetron blocked 5 -HT3 receptors longer than zatosetron, whereas N-desmethylzatosetron s howed 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-beta-N-oxide. Zatosetron-bet a-N-oxide had approximately 100-fold lower 5-HT3 receptor affinity rel ative to zatosetron and was approximately 150-fold less active as an a ntagonist at 5-HT3 receptors in vivo (ED50 = 115 mug/kg iv). Thus, alt hough pharmacological activity was observed with all four metabolites, they were all less active in vivo than zatosetron. Therefore, these m etabolites would contribute significantly to the activity of zatosetro n only if plasma (and tissue) levels greatly exceeded those of zatoset ron. (C) 1993 Wiley-Liss, Inc.