MEMBRANE-TRANSPORT AS A DETERMINANT OF THE HEPATIC ELIMINATION OF DRUGS AND METABOLITES

1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the b asolateral membrane occurs via passive diffusion, with minimal relianc e on carrier-mediated transport systems. Often, this passive diffusion is so efficient that uptake is rate-limited by the delivery of the dr ug to the liver (i.e. blood flow) rather than membrane transport per s e. 2. For highly polar molecules, passive diffusion no longer represen ts an efficient mode of hepatocellular uptake and there is an increase d reliance on carrier-mediated transport systems. Fbr these compounds, membrane transport may dictate the overall efficiency of hepatic elim ination. 3. Drug metabolites, particularly conjugated metabolites, suc h as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as d iffusional barriers. In the presence of such a barrier, the hepatocell ular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier-mediated transport systems for s inusoidal efflux and biliary excretion. Transporters of current intere st include P-glycoproteins, which are responsible for the biliary excr etion of a range of organic cations, and the canalicular multispecific organic anion transporter. 4. Intracellular trapping of hepatically f ormed metabolites, secondary to low membrane permeability, is clinical ly important as many metabolites are potentially hepatotoxic and/or ca pable of interfering with the hepatic transport of endogenous compound s or other drugs and metabolites. In addition, if the metabolite is un stable, intracellular accumulation can lead to the regeneration of the precursor and 'futile cycling' within hepatocytes. 5. An increased un derstanding of the factors influencing the intracellular concentration s of drugs and hepatically formed metabolites in the liver will improv e our ability to specifically treat liver disorders, such as hepatocel lular carcinoma and malaria, and minimize the risk of hepatotoxicity f rom drugs and other xenobiotics.