Active reabsorption of important substances that have been filtered at the glomerular membranes. The transport mechanism is in the luminal portion of the membrane of the proximal tubular cell. Solid arrow indicates active transport.

cretion, while high doses have a uricosuric effect. This is offered as an explanation for the apparently paradoxical effects of low and high doses of drugs on the total excretory pattern of compounds that are handled by renal active transport.

Clinical Implications of Renal Excretion

The rate of urinary drug excretion will depend on the drug's volume of distribution, its degree of protein binding, and the following renal factors:

1. Glomerular filtration rate

2. Tubular fluid pH

3. Extent of back-diffusion of the unionized form

4. Extent of active tubular secretion of the compound

5. Possibly, extent of active tubular reabsorption

Changes in any of these factors may result in clinically important alterations in drug action. In the final analysis, the amount of drug that finally appears in the urine will represent a balance of filtered, reabsorbed (passively and actively), and secreted drug. For many drugs, the duration and intensity of pharmacological effect will be influenced by the status of renal function, because of the major role played by the kidneys in drug and metabolite elimination. Ultimately, whether or not dosage adjustment (e.g., prolongation of dosing interval, reduction in the maintenance dose, or both) becomes necessary will depend on an assessment of the degree of renal dysfunction, the percentage of drug cleared by the kidney, and the potential for drug toxic-ity, especially if renal function is reduced.

Biliary Excretion

The liver secretes about 1 L of bile daily. Bile flow and composition depend on the secretory activity of the hepatic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composition can be modified in the ductules and ducts by the processes of reabsorption and secretion, especially of electrolytes and water. For example, osmotically active compounds, including bile acids, transported into the bile promote the passive movement of fluid into the duct lumen. In the gallbladder, composition of the bile is modified further through reabsorptive processes.

The passage of most foreign compounds from the blood into the liver normally is not restricted because the endothelium of the hepatic blood sinusoids behaves as a porous membrane. Hence, drugs with molecular weights lower than those of most protein molecules readily reach the hepatic extracellular fluid from the plasma. A number of compounds are taken up into the liver by carrier-mediated systems, while more lipophilic drugs pass through the hepatocyte membrane by diffusion. The subsequent passage of substances into the bile, however, is much more selective.

At least three groups of compounds enter the bile. Compounds of group A are those whose concentration in bile and plasma are almost identical (bile-plasma ratio of 1). These include glucose, and ions such as Na+, K+, and Cl". Group B contains the bile salts, bilirubin glucuronide, sulfobromophthalein, procainamide, and others, whose ratio of bile to blood is much greater than 1, usually 10 to 1,000. Group C is reserved for compounds for which the ratio of bile to blood is less than 1, for example, insulin, sucrose, and proteins. Drugs can belong to any of these three categories. Only small amounts of most drugs reach the bile by diffusion. However, biliary excretion plays a major role (5-95% of the administered dose) in drug removal for some anions, cations, and certain un-ionized molecules, such as cardiac glycosides. In addition, biliary elimination may be important for the excretion of some heavy metals.

Cardiac glycosides, anions, and cations are transported from the liver into the bile by three distinct and independent carrier-mediated active transport systems, the last two closely resembling those in the renal proximal tubules that secrete anions and cations into tubular urine. As is true for renal tubular secretion, protein-bound drug is completely available for biliary active transport. In contrast to the bile acids, the actively secreted drugs generally do not recycle, because they are not substrates for the intestinal bile acid transport system, and they are generally too highly charged to backdiffuse across the intestinal epithelium. Thus, the ability of certain compounds to be actively secreted into bile accounts for the large quantity of these drugs removed from the body by way of the feces.

On the other hand, most drugs that are secreted by the liver into the bile and then into the small intestine are not eliminated through the feces. The physicochem-ical properties of most drugs are sufficiently favorable for passive intestinal absorption that the compound will reenter the blood that perfuses the intestine and again be carried to the liver. Such recycling may continue (en-terohepatic cycle or circulation) until the drug either undergoes metabolic changes in the liver, is excreted by the kidneys, or both. This process permits the conservation of such important endogenous substances as the bile acids, vitamins D3 and B12, folic acid, and estrogens (Table 4.6).

Extensive enterohepatic cycling may be partly responsible for a drug's long persistence in the body. Orally administered activated charcoal and/or anion exchange resins have been used clinically to interrupt en-terohepatic cycling and trap drugs in the gastrointestinal tract.

As stated earlier, many foreign compounds are either partially or extensively metabolized in the liver.

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