QUANTITATIVE PREDICTION OF IN-VIVO DRUG CLEARANCE AND DRUG-INTERACTIONS FROM IN-VITRO DATA ON METABOLISM, TOGETHER WITH BINDING AND TRANSPORT

It is of great importance to predict in vivo pharmacokinetics in human s based on in vitro data. We summarize recent findings of the quantita tive prediction of the hepatic metabolic clearance from in vitro studi es using human liver microsomes, hepatocytes, or P450 isozyme recombin ant systems. Furthermore, we propose a method to predict pharmacokinet ic alterations caused by drug-drug interactions that is based on in vi tro metabolic inhibition studies using human liver microsomes or human enzyme expression systems. Although we attempt to avoid the false neg ative prediction, the inhibitory effect was underestimated in some cas es, indicating the possible contribution of the active transport into hepatocytes and/or interactions at the processes other than the hepati c metabolism, such as the metabolism and transport processes during ga strointestinal absorption.