This review illustrates the concept of a rate-determining process in the overall hepatic elimination of anionic drugs that involves transporters in the uptake process. A kinetic study in rats has demonstrated that uptake is the rate-determining process for most anionic drugs, and this is likely to hold true for the hepatic elimination of statins in humans. To simulate the effects of variations in the transporter activities on systemic and liver exposure, a physiologically based pharmacokinetic model was constructed for pravastatin, the overall elimination of which involves OATP1B1 and MRP2 in the hepatic uptake and canalicular efflux, respectively. The plasma concentrations of pravastatin in humans were successfully reproduced using the kinetic parameters extrapolated from in vitro data obtained using human hepatocytes and canalicular membrane vesicles and the scaling factors determined in rats. Sensitivity analyses showed that a variation in hepatic uptake altered the plasma concentration of pravastatin markedly, but had a small effect on the liver concentration, and vice versa for the canalicular efflux. Therefore, variation in the OATP1B1 activities will have small and large impacts on the therapeutic efficacy and adverse effect (myopathy) of pravastatin, respectively, whereas that affecting the MRP2 activities may have an opposite effect (i.e., large and small impacts on the therapeutic efficacy and side effect). This pharmacokinetic characteristics likely hold true for other anionic statins, i.e., variation of OATP1B1 is associated with the risk of adverse reactions, whereas that of sequestration mechanisms causes the variation of their pharmacological effect.