Drug Elimination V

Enterohepatic Cycle
After an orally ingested drug has been
absorbed from the gut, it is transported
via the portal blood to the liver, where it
can be conjugated to glucuronic or sulfuric
acid (shown in B for salicylic acid
and deacetylated bisacodyl, respectively)
or to other organic acids. At the pH of
body fluids, these acids are predominantly
ionized; the negative charge confers
high polarity upon the conjugated
drug molecule and, hence, low membrane
penetrability. The conjugated
products may pass from hepatocyte into
biliary fluid and from there back into
the intestine. O-glucuronides can be
cleaved by bacterial !-glucuronidases in
the colon, enabling the liberated drug
molecule to be reabsorbed. The enterohepatic
cycle acts to trap drugs in the
body. However, conjugated products
enter not only the bile but also the
blood. Glucuronides with a molecular
weight (MW) > 300 preferentially pass
into the blood, while those with MW >
300 enter the bile to a larger extent.
Glucuronides circulating in the blood
undergo glomerular filtration in the kidney
and are excreted in urine because
their decreased lipophilicity prevents
tubular reabsorption.
Drugs that are subject to enterohepatic
cycling are, therefore, excreted
slowly. Pertinent examples include digitoxin
and acidic nonsteroidal anti-inflammatory
agents .