Polar Sulfate Conjugates



Conjugation of a compound or its metabolites is especially important in determining whether the drug will undergo biliary excretion. Frequently, when a compound is secreted into the intestine through the bile, it is in the form of a conjugate. Conjugation generally enhances biliary excretion, since it both introduces a strong polar (i.e., anionic) center into the molecule and increases its molecular weight. Molecular weight may, however, be less important in the biliary excretion of organic cations. Conjugated drugs will not be reabsorbed readily from the gastrointestinal tract unless the conjugate is hydrolyzed by gut enzymes such as p-glucuronidase. Chloramphenicol glucuronide, for example, is secreted into the bile, where it is hydrolyzed by gastrointestinal flora and largely reabsorbed. Such a continuous recirculation may lead to the appearance of drug-induced toxicity.

The kidney and liver are, in general, capable of actively transporting the same organic anion substrates. However, the two organs have certain quantitative differences in drug affinity for the transporters. It has been suggested that several subsystems of organic anion transport may exist and that the binding specificities of the transporters involved are not absolute but overlapping.

Liver disease or injury may impair bile secretion and thereby lead to accumulation of certain drugs, for example probenecid, digoxin, and diethylstilbestrol. Impairment of liver function can lead to decreased rates of both drug metabolism and secretion of drugs into bile. These two processes, of course, are frequently interrelated, since many drugs are candidates for biliary secretion only after appropriate metabolism has occurred.

Decreases in biliary excretion have been demonstrated at both ends of the age continuum. For example, ouabain, an unmetabolized cardiac glycoside that is secreted into the bile, is particularly toxic in the newborn. This is largely due to a reduced ability of biliary secretion to remove ouabain from the plasma.

Increases in hepatic excretory function also may take place. After the chronic administration of either phenobarbital or the potassium-sparing diuretic spirono-

lactone, the rate of bile flow is augmented. Such an increase in bile secretion can reduce blood levels of drugs that depend on biliary elimination.

Finally, the administration of one drug may influence the rate of biliary excretion of a second coadministered compound. These effects may be brought about through an alteration in one or more of the following factors: hepatic blood flow, uptake into hepatocytes, rate of biotransformation, transport into bile, or rate of bile formation. In addition, antibiotics may alter the intestinal flora in such a manner as to diminish the presence of sulfatase and glucuronidase-containing bacteria. This would result in a persistence of the conjugated form of the drug and hence a decrease in its enterohepatic recirculation.

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