The metabolism of the 5HT₃ antagonists, ondansetron, alosetron and GR87442 II: Investigation into the in vitro methods used to predict the in vivo hepatic clearance of ondansetron, alosetron and GR87442 in the rat, dog and human

Abstract

The in vitro clearances of the 5HT₃ antagonists, ondansetron, alosetron and GR87442 were investigated. Intrinsic clearances using either metabolite formation or substrate depletion methods were equivalent (R² = 0.95). Hepatocytes from preclinical species were superior to microsomes for the prediction of hepatic clearance (CL_H), whereas the predictions from human microsomes and hepatocytes were similar. Using a non-restrictive model, seven of the nine CL_H predictions using hepatocytes were within 2-fold of the in vivo CL_H values. If the unbound fraction was included, the clearance of the compounds was generally under-predicted by both in vitro models. However, for the most metabolically stable compound, GR87442, the non-restrictive model over-predicted CLp. This and the possibility of extrahepatic metabolism indicate that the restrictive model is more appropriate for prediction of CL_H. The rank order of metabolic stability correlated with that in vivo. All three compounds were more metabolically stable in human than in the preclinical animal species examined.

Key Words::

• 5-HT₃ Antagonists
• hepatocytes
• microsomes
• hepatic clearance

Acknowledgement

The authors thank Nicola J. Hewitt for her help in the preparation of this manuscript.