The Liver as an Excretory Organ

As the chief organ of drug biotransfor-mation, the liver is richly supplied withblood, of which 1100 mL is receivedeach minute from the intestinesthrough the portal vein and 350 mLthrough the hepatic artery, comprisingnearly 1/3 of cardiac output. The bloodcontent of hepatic vessels and sinusoidsamounts to 500 mL. Due to the widen-ing of the portal lumen, intrahepaticblood flow decelerates. Moreover,the endothelial lining of hepatic sinu-soids contains pores largeenough to permit rapid exit of plasmaproteins. Thus, blood and hepatic paren-chyma are able to maintain intimatecontact and intensive exchange of sub-stances, which is further facilitated bymicrovilli covering the hepatocyte sur-faces abutting Disse’s spaces.The hepatocyte secretes biliaryfluid into the bile canaliculi (darkgreen), tubular intercellular clefts thatare sealed off from the blood spaces bytight junctions. Secretory activity in thehepatocytes results in movement offluid towards the canalicular space.The hepatocyte has an abundance of en-zymes carrying out metabolic functions.These are localized in part in mitochon-dria, in part on the membranes of therough (rER) or smooth (sER) endoplas-mic reticulum.Enzymes of the sER play a most im-portant role in drug biotransformation.At this site, molecular oxygen is used inoxidative reactions. Because these en-zymes can catalyze either hydroxylationor oxidative cleavage of -N-C- or -O-C-bonds, they are referred to as “mixed-function” oxidases or hydroxylases. Theessential component of this enzymesystem is cytochrome P450, which in itsoxidized state binds drug substrates (R-H). The FeIII-P450-RH binary complex isfirst reduced by NADPH, then forms theternarycomplex,O2-FeII-P450-RH,which accepts a second electron and fi-nally disintegrates into FeIII-P450, oneequivalent of H2O, and hydroxylateddrug (R-OH).

Compared with hydrophilic drugsnot undergoing transport, lipophilicdrugs are more rapidly taken up fromthe blood into hepatocytes and morereadily gain access to mixed-functionoxidases embedded in sER membranes.For instance, a drug having lipophilicityby virtue of an aromatic substituent(phenyl ring) can be hydroxylatedand, thus, become more hydrophilic. Besides oxi-dases, sER also contains reductases andglucuronyl transferases. The latter con-jugate glucuronic acid with hydroxyl,carboxyl, amine, and amide groups; hence, also phenolic products ofphase I metabolism (Phase II conjuga-tion). Phase I and Phase II metabolitescan be transported back into the blood— probably via a gradient-dependentcarrier — or actively secreted into bile.Prolonged exposure to certain sub-strates, such as phenobarbital, carbama-zepine, rifampicin results in a prolifera-tion of sER membranes.This enzyme induction, a load-depen-dent hypertrophy, affects equally all en-zymes localized on sER membranes. En-zyme induction leads to acceleratedbiotransformation, not only of the in-ducing agent but also of other drugs (aform of drug interaction). With contin-ued exposure, induction develops in afew days, resulting in an increase in re-action velocity, maximally 2–3 fold, thatdisappears after removal of the induc-ing agent.