PRINCIPLES OF TOXICOLOGY

52 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTS
Thus, lipid-soluble compounds are subject to reabsorption after having been filtered by the kidney.
The degree of reabsorption of electrolytes will be strongly influenced by the pH of the urine, which
determines the amount of the chemical present in a nonionized form.
It is to be expected that some control could be exerted over the rate of excretion of weak acids and
bases by adjusting urine pH. This type of treatment can be used very effectively in some cases.
Alkalinization of the urine by administration of bicarbonate has been used to treat salicylic acid
poisoning in humans. Alkalinization causes the weak acid to become more fully ionized; the ionized
molecule is excreted in the urine rather than reabsorbed.
There are also active secretory and reabsorptive processes in the renal tubules of the kidney. These
processes are specialized to handle endogenous compounds; active reabsorption helps to conserve the
essential nutrients, glucose and amino acids. These pathways can also be used by exogenous
compounds, provided the compounds have the structural and electronic configurations required by the
carrier molecules.
The renal clearance represents a hypothetical plasma volume cleared of solute by the net action of
all renal mechanisms during the specified period of time. A compound such as creatinine that is filtered
but not secreted or reabsorbed is cleared in adult humans at a rate of about 125 mL/min. Compounds
that are reabsorbed as well as filtered have clearances less than the creatinine clearance. Compounds
that are actively secreted can have clearances as large as the renal plasma flow, about 600 mL/min.
The presence of disease in the kidney can affect the half-life of a compound eliminated via the
kidney, just as the presence of disease in the liver can affect the half-life of a compound that is largely
biotransformed.
Excretion in the Liver The liver is both the major metabolizing organ and a major excretory organ.
Large fractions of many toxicants absorbed from the gastrointestinal tract are eliminated in the liver
by metabolism or excretion before they can reach the systemic circulation, the hepatic first-pass effect.
In addition, metabolites formed in the liver may be excreted into the bile before they themselves have
had a chance to circulate. Although it does not excrete as many different compounds as the kidney
does, the liver is in an advantageous position with regard to excretion, particularly of metabolites.
There are at least three active systems for transport of organic compounds from liver into bile: one
for acids, one for bases, and one for neutral compounds. Certain metals are also excreted into bile
against a concentration gradient. These transport processes are efficient and can extract protein-bound
as well as free chemicals. The characteristics that determine whether a compound will be excreted in
the bile or in the urine include its molecular weight, charge, and charge distribution. In general, highly
polar and larger compounds are more frequently found in the bile. The threshold molecular weight for
biliary excretion is species-dependent. In the rat, compounds with molecular weights greater than about
350 can be excreted in the bile. Those having molecular weights greater than about 450 are excreted
predominantly in the bile, while compounds with molecular weights between 350 and 450 are
frequently found in both urine and bile.
Once a compound has been excreted by the liver into the bile, and thereby into the intestinal tract,
it can either be excreted in the feces or reabsorbed. Most frequently the excreted compound itself,
being water-soluble, is not likely to be reabsorbed directly. However, glucuronidase enzymes of the
intestinal microflora are capable of hydrolyzing glucuronides, releasing less polar compounds that
may then be reabsorbed. The process is termed enterohepatic circulation. It can result in extended
retention of compounds recycled in this manner. Techniques have been developed to interrupt the
enterohepatic cycle by introducing an adsorbent that will bind the excreted chemical and carry it
through the gastrointestinal tract.
Certain factors influence the efficiency of liver excretion. Liver disease can reduce the excretory
as well as the metabolic capacity of the liver. On the other hand, a number of drugs increase the rate
of hepatic excretion by increasing bile flow rate. For example, phenobarbital produces an increase in
bile flow that is not related to its ability to induce metabolizing enzymes. Whether the increased rate
of bile flow will increase the rate of elimination of a compound that is both metabolized and excreted
by the liver depends on whether the rate-limiting step is the enzyme-catalyzed biotransformation or