Biotransformation of the antiemetic 5-HT3 antagonist tropisetron in liver and kidney slices of human, rat and dog with a comparison to in vivo

Abstract

Species differences in the biotransformation of the antiemetic tropisetron, a potent 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, were evident in liver slice incubates of human, rat and dog, and reflected the species differences observed in vivo with respect to the relative importance of individual pathways. The dominant biotransformation pathway of tropisetron (10 microM) in human liver slices was formation of 6-hydroxy-tropisetron, whereas in rat liver slices it was 5-hydroxy-tropisetron, and in dog liver slices N-oxide formation. Initial rates of tropisetron metabolite formation in the liver slices (8 mm in diameter, 200 +/- 25 microns 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 prediction matched well with the species ranking of tropisetron bioavailability; however, for dog the in vitro data overestimated the apparent first-pass effect. The jejunum is not expected to contribute to the first-pass effect in humans, since human jejunum microsomes did not metabolize tropisetron. The major organ of excretion for tropisetron and its metabolites is the kidney, but the contribution of the kidney to the overall metabolism of tropisetron would be small. Species independent N-oxide formation (2-12 pmol/h/mg slice protein) was the major pathway in human, rat and dog kidney slices, and was comparable to N-oxide formation in the rat and human liver slices but was 1/10 the rate in dog liver slices. This study has demonstrated that the liver is the primary site of tropisetron biotransformation, and the usefulness of organ slices to characterize cross species differences in the dominant biotransformation pathways.

In Vivo Dose and Duration Dependent Effects of a Dioxin (2,3,7,8 TCDD) on Few Lysosomal Enzymes in Mice Brain

“…Highly significant variation were observed in α-galactosidase activity in brain tissue (64.08, p = 0.05). TCDD and related compounds are reported to bind with cytoplasmic AhR receptors and known to disrupt the glucuronyl transferase activity by affecting different gene expression [29] . Such type of environmental factors are found to be in low concentration in brain whilst these affects to cellular mechanism leading to metabolic pathway [30] .…”

Evaluation of Microsomal Incubation Conditions on CYP3A4-Mediated Metabolism of Cyclosporine A by a Statistical Experimental Design

“…The design variables and their settings (high and low values in the design) were selected on the basis of variations in previously reported microsomal incubation conditions for CsA [14][15][16][17]. Both Tris-and phosphate buffers have previously been applied [16,17].…”

“…1), and is one out of eight recommended CYP3A4 probes in current guidelines [4,5]. The variety of microsomal incubation conditions used in former studies on CYP3A4 metabolism of CsA was applied as limits for the statistical experimental design [14][15][16][17].…”

The metabolism of the 5HT3antagonists, ondansetron, alosetron and GR87442 II: Investigation into thein vitromethods used to predict thein vivohepatic clearance of ondansetron, alosetron and GR87442 in the rat, dog and human

“…The possibility of extrahepatic metabolism of these compounds exists as indicated by a plasma clearance of ondansetron that exceeds hepatic blood flow. In addition, extrahepatic metabolism has previously been reported for molecules in this structural class (Vickers et al 1996). These data coupled with the over-prediction of the plasma clearance of GR87442 when using non-restrictive models may indicate that protein binding should indeed be incorporated and that under-predictions of plasma clearance should be expected for compounds with extrahepatic metabolism.…”

“…In preclinical species and humans, ondansetron, alosetron and GR87442 are primarily cleared by metabolism via a number of oxidative phase I pathways followed by phase II conjugation. The plasma clearance is primarily hepatic but extrahepatic metabolism has reported to be involved in the overall metabolism of these compounds (Vickers et al 1996). Although structurally similar, the three compounds have markedly different rates of hepatic clearance in animals and humans (Table I).…”