Strategies to Improve Pharmacokinetics of Hepatic Uptake Transporter Substrates

For hepatic uptake transporter substrates, hepatic clearance depends not only on the rates of elimination (metabolism and biliary excretion) but also on the rates at which a drug moves between the liver and bloodstream. With representative extended clearance classification system Class 1B drugs, we performed mouse in vivo studies with chemical inhibitors of metabolism and hepatic uptake to demonstrate how permeability affects the relative contributions of hepatic uptake and metabolism to clearance. In addition, we show how half-life can be extended through reductions in metabolism but is largely unaffected by changes in hepatic uptake. Insights from the extended clearance model and pharmacokinetic modeling are used to supplement these studies. While most literature focuses on reducing hepatic uptake as the main strategy to reduce clearance for this class of drugs, we present a rationale to reduce clearance and extend half-life by increasing permeability and reducing metabolism.