Effect of a diffusional barrier to a metabolite across hepatocytes on its kinetics in "enzyme-distributed" models: a computer-aided simulation study.
The effect of a diffusional barrier to a metabolite between the blood and hepatocytes on elimination kinetics of formed and preformed metabolites was predicted under various enzymic distributions in the liver by computer-aided simulation. Sequential metabolism by which the primary metabolite (MI) is generated from the parent drug (D) and further metabolized to the terminal metabolite (MII) by enzymes A and B, respectively, was chosen for the simulation. Moreover, four models of enzyme distribution patterns were defined with regard to the hepatic blood flow path. The extraction ratios for the preformed and formed metabolites (designated as Em and Ep----m, respectively) were simulated by varying both the average intrinsic clearance of enzyme B (CLint,B) and the permeability of hepatocytes for MI (Pm), while keeping the average intrinsic clearance of enzyme A (CLint,A) equal to hepatic blood flow (Q). When a rapid equilibrium of MI between the blood and hepatocytes held, i.e., Pm was large relative to Q, Em was equal to or higher than Ep----m for all models, as previously shown by Pang and Stillwell. By contrast, it was found that when a diffusional barrier for MI existed, i.e., Pm was small relative to Q, Em was equal to or lower than Ep----m. Furthermore, it was observed that the smaller Pm became, the larger the difference between Em and Ep----m became. We further simulated the effect of the intrinsic clearance (CLint,C) for a metabolic pathway, which competes for that by enzyme A, on the Ep----m value. In the model assuming even distribution of all the enzymes along the flow path, irrespective of the CLint,C value, a similar effect of Pm on Ep----m was observed when the Pm value was relatively small (Pm less than Q). By contrast, in the case of uneven enzymic distributions of enzymes A and B, the effect of the CLint,C value on the relationship between Pm and Ep----m occurred to some extent. From these simulations, it was concluded that lower membrane permeability (Pm) both diminishes the entry of preformed metabolite into the hepatocytes and accelerates the removal of intracellularly formed metabolite (through sequential metabolism) by diminishing its efflux, yielding lower Em than Ep----m. When Pm becomes small (Pm less than 1/10Q), these mechanisms for lower Em than Ep----m predominate over other mechanisms such as the presence of a competing metabolic route and uneven distribution of enzymes.
Miyauchi
S
S
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Sugiyama
Y
Y
Sato
H
H
Sawada
Y
Y
Iga
T
T
Hanano
M
M
D001711:Biotransformation; D003198:Computer Simulation; D004058:Diffusion; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D010539:Permeability; D010599:Pharmacokinetics