INTERSPECIES SCALING OF TOLCAPONE, A NEW INHIBITOR OF CATECHOL-O-METHYLTRANSFERASE (COMT) - USE OF IN-VITRO DATA FROM HEPATOCYTES TO PREDICT METABOLIC-CLEARANCE IN ANIMALS AND HUMANS

1. In the present study, in vivo pharmacokinetic data in animals were combined with in vitro metabolic data from animal and human hepatocyte s to predict the human systemic plasma clearance and the kinetic profi le of tolcapone, a compound metabolized by phase II reactions. 2. The integration of in vitro metabolic data from hepatocytes into allometri c scaling gave satisfactory predictions of metabolic clearance in huma ns for tolcapone (74.2 ml/min predicted versus 118 ml/min observed). 3 . Using combined time transformations and in vitro metabolic rates, th e range of values predicted from the various animal species (90.4 to 2 42 ml/min, 0.60 to 2.2 h and 7.3 to 121 for clearance, half-life and v olume of distribution, respectively) were in good agreement with the o bserved values in humans (118 ml/min, 1.3 h and 8.61, respectively). 4 . Compared to the conventional correction factors (e.g. maximum life s pan, brain weight), in vitro metabolic data provide a more rational ba sis for extrapolating the metabolic clearance in humans.