Interspecies scaling of bosentan, a new endothelin receptor antagonist and integration of in vitro data into allometric scaling.
OBJECTIVE
The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans.


METHODS
One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling.


RESULTS
The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight).


CONCLUSIONS
This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.
Lave
T
T
Hoffmann-LaRoche, Basel, Switzerland.
Coassolo
P
P
Ubeaud
G
G
Brandt
R
R
Schmitt
C
C
Dupin
S
S
Jaeck
D
D
Chou
R C
RC
D000818:Animals; D000077300:Bosentan; D002144:Callithrix; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D006801:Humans; D016014:Linear Models; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013449:Sulfonamides / Q000493:pharmacokinetics*
D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan