Abstract
Elucidation of the rate-determining process in the overall hepatic elimination of drugs is critical for predicting their intrinsic hepatic clearance, and the impact of variation of sequestration clearance on their systemic concentration. The present study investigated the rate-determining process in the overall hepatic elimination of the HMG-CoA reductase inhibitors, pravastatin, pitavastatin, atorvastatin, and fluvastatin, both in rats and humans. The uptake of these statins was saturable in both rat and human hepatocytes. Intrinsic hepatic clearance obtained by in vivo pharmacokinetic analysis in rats was close to the uptake clearance determined by the multiple indicator dilution method but much greater than the intrinsic metabolic clearance extrapolated from an in vitro model using liver microsomes. In vivo uptake clearance of the statins in humans (pravastatin 1.44, pitavastatin 30.6, atorvastatin 12.7, and fluvastatin 62.9 ml/min/g liver), which was obtained by multiplying in vitro uptake clearance determined in cryopreserved human hepatocytes by rat scaling factors, were within the range of overall in vivo intrinsic hepatic clearance (pravastatin 0.84-1.2, pitavastatin 14-35, atorvastatin 11-19, and fluvastatin 123-185 ml/min/g liver), whereas the intrinsic metabolic clearance of atorvastatin and fluvastatin were considerably low compared with their intrinsic hepatic clearance. Their uptake is the rate-determining process in the overall hepatic elimination of the statins in rats, and this likely holds true in humans. In vitro-in vivo extrapolation of the uptake clearance using a cryopreserved human hepatocytes model and rat scaling factors will be effective for predicting in vivo intrinsic hepatic clearance involving active uptake.
- drug transport
- hepatic elimination
- hepatobiliary transport
- hepatocytes
- in vitro-in vivo prediction
- in vitro-in vivo scaling
- organic anion transport
- transporters
Footnotes
- Received September 16, 2009.
- Accepted October 23, 2009.
- The American Society for Pharmacology and Experimental Therapeutics