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 enzymic distribution patterns were defined with regard to the hepatic blood flow path. The extraction ratios for the preformed and formed metabolites (designated as E_m and E_p→m, respectively) were simulated by varying both the average intrinsic clearance of enzyme B ( $\overline {CL_{int,B} }$ ) and the permeability of hepatocytes for MI ( $\overline {P_m }$ ), while keeping the average intrinsic clearance of enzyme A ( $\overline {CL_{int,A} }$ ) equal to hepatic blood flow (Q). When a rapid equilibrium of MI between the blood and hepatocytes held, i.e., $\overline {P_m }$ was large relative to Q, E_m was equal to or higher than E_p→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., $\overline {P_m }$ was small relative to Q, E_m was equal to or lower than E_p→m. Furthermore, it was observed that the smaller $\overline {P_m }$ became, the larger the difference between E_m and E_p→m became. We further simulated the effect of the intrinsic clearance ( $\overline {CL_{int,C} }$ ) for a metabolic pathway, which competes for that by enzyme A. on the E _p→m value. In the model assuming even distribution of all the enzymes along the flow path, irrespective of the $\overline {CL_{int,C} }$ value, a similar effect of $\overline {P_m }$ on E_p→m was observed when the $\overline {P_m }$ value was relatively small ( $\overline {P_m }< Q$ ). By contrast, in the case of uneven enzymic distributions of enzymes A and B, the effect of the $\overline {CL_{int,C} }$ value on the relationship between P_m and E_p→m occurred to some extent. From these simulations, it was concluded that lower membrane permeability ( $\overline {P_m }$ ) 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 E_m than E_p→m. When $\overline {P_m }$ becomes small ( $\overline {P_m }< 1/10Q$ ), these mechanisms for lower E_m than E_p→m predominate over other mechanisms such as the presence of a competing metabolic route and uneven distribution of enzymes.