Abstract
Accurately predicting in vivo metabolic clearance from in vitro liver microsomes or hepatocytes requires a good understanding of the factors contributing to the prediction. While much work has concentrated on deriving scaling factors and optimising the metabolic stability techniques for consistency and rigour it is only relatively recently that the importance of binding to microsomes and hepatocytes has been appreciated. Ultrafiltration is often used to estimate binding to plasma proteins and microsomes but the level of non-specific binding (NSB) to the ultrafiltration apparatus has not been adequately described. We derive an equation to correct for NSB and demonstrate that this can significantly affect the estimate of binding to microsomes and improve the accuracy of scaling to in vivo clearance for a series of barbiturates.
- Received June 10, 2011.
- Accepted August 31, 2011.
- The American Society for Pharmacology and Experimental Therapeutics