Biomedical Engineering Reference
In-Depth Information
13.1. HEPATIC PHYSIOLOGY: LIVER STRUCTURE AND FUNCTION
The liver is one of the major organs involved in drug metabolism and excretion. Hep-
atocytes, which are the predominant cell type in the liver, are polarized cells with
distinct basolateral and apical domains that extend in chordlike arrays throughout the
liver (see Figure 13.1). Hepatoctyes contain the principal metabolic and transport ma-
chinery responsible for hepatic drug clearance. Transport proteins play an important
role in the clearance of drugs from hepatic sinusoidal blood and the excretion of parent
compound and/or metabolite(s) across the apical membrane into the bile canaliculus.
Although lipophilic compounds may diffuse from sinusoidal blood across the basolat-
eral (sinusoidal and lateral) membrane domain, it is now recognized that many drugs
gain access to the hepatocyte via transport proteins. Biliary excretion of drugs and
metabolites is an active process that requires adenosine triphosphate (ATP)-dependent
transport proteins that pump substrates into the canalicular lumen. ATP-dependent
transport proteins also aid in the removal of drugs and metabolites from the hepato-
cyte by pumping them across the basolateral membrane into sinusoidal blood as it
flows toward the central vein.
The field of hepatic transport is an emerging discipline. In the sections that follow,
hepatic transport proteins are introduced based on their localization and function as
(a)
Tight junction
ìBloodî
ìBileî
Collagen
layers
hepatocyte
(b)
Bile canaliculus
FIGURE13.1.
(
a
) In vivo architecture of the liver and polarized nature of hepatocytes, display-
ing two separate membrane domains facing blood and bile;
(b)
scheme illustrating the polarized
phenotype in vitro when hepatocytes are cultured in a sandwich configuration (between two
layers of gelled collagen). [(
a
) In part according to ref. 278, with permission.]
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