BIOTRANSFORMATION OF THE ANTIEMETIC 5-HT3 ANTAGONIST TROPISETRON IN LIVER AND KIDNEY SLICES OF HUMAN, RAT AND DOG WITH A COMPARISON TO IN-VIVO

Species differences in the biotransformation of the antiemetic tropise tron, a potent 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, were evident in liver slice incubates of human, rat and dog, and refl ected the species differences observed in vivo with respect to the rel ative importance of individual pathways, The dominant biotransformatio n pathway of tropisetron (10 mu M) in human liver slices was formation of 6-hydroxy-tropisetron, whereas in rat liver slices it was 5-hydrox y-tropisetron, and in dog liver slices N-oxide formation. Initial rate s of tropisetron metabolite formation in the liver slices (8 mm in dia meter, 200 +/- 25 mu m thickness) of human (83 +/- 61 pmol/h/mg slice protein), rat (413 +/- 98 pmol/h/mg slice protein) and dog (426 +/- 38 pmol/h/mg slice protein) would predict less of a first-pass effect in humans compared to the rat or the dog. For human and rat, the predict ion matched well with the species ranking of tropisetron bioavailabili ty; however, for dog the in vitro data overestimated the apparent firs t-pass effect. The jejunum is not expected to contribute to the first- pass effect in humans, since human jejunum microsomes did not metaboli ze tropisetron. The major organ of excretion for tropisetron and its m etabolites is the kidney, but the contribution of the kidney to the ov erall metabolism of tropisetron would be small. Species independent N- oxide formation (2-12 pmol/h/mg slice protein) was the major pathway i n human, rat and dog kidney slices, and was comparable to N-oxide form ation in the rat and human liver dices but was 1/10 the rate in dog li ver slices. This study has demonstrated that the liver is the primary site of tropisetron biotransformation, and the usefulness of organ sli ces to characterize cross species differences in the dominant biotrans formation pathways.