Phase-3 Detoxification in the Liver: Biliary Excretion of small molecules and peptides by primary active transport mechanisms

Abstract

Recently, for many endogenous and exogenous compounds(including drugs), it has been reported that carrier-mediated primary active transport contributes to biliary excretion. Compounds known to be excreted by this mechanism are anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic anid conjugates. Primary active excretion into bile means the positive removal of xenobiotics from the body, and the elimination process is now designated as “Phase III” (T.Ishikawa, Trends Biochem.Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. There exist multiplicities in the biliary excretion mechanisms. Clarification of these multiplicities in transport is necessary not just from a biochemical point of view, but for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. This may provide a lot of important informations for studying the pharmacokinetics of new drugs. In this presentation, I would like to summarize the latest experimental results on carrier-mediated biliary excretion systems and the multiplicities in the biliary excretion of xenobiotics, including small peptides.