Received for publication September 26, 2008.
Revised November 6, 2008.
Accepted for publication November 7, 2008.

Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans

Abstract

Hepatobiliary excretion mediated by transporters, OATP1B1 and MRP2, is the major elimination pathway of an HMG-Co A reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained. The simulated plasma and liver concentrations, and biliary excretion profiles were very close to the observed data in rats under linear and nonlinear conditions. In vitro parameters, determined in human cryopreserved hepatocytes and canalicular membrane vesicles, were extrapolated to in vivo parameters using the scaling factors obtained in rats. The simulated plasma concentrations of pravastatin were close to the reported values in humans. Sensitivity analyses showed that changes in the hepatic uptake ability altered the plasma concentration of pravastatin markedly, but had a minimal effect on the liver concentration, while changes in the ability of canalicular efflux altered the liver concentration of pravastatin markedly, but had a small effect on the plasma concentration. In conclusion, the model allows the prediction of the disposition of pravastatin in humans. The present study suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect (myopathy) of pravastatin, respectively, whereas those in the MRP2 activities may have opposite impacts (i.e., a large and a small impact on the therapeutic efficacy and side effect).

Key words: cholesterol lowering effect, hepatobiliary transport, physiologically based pharmacokinetic model, pravastatin, rhabdomyolysis, transporter