Although some drugs are excreted through extrarenal pathways, the kidney is the primary organ of removal for most drugs (Figure 4.2), especially for those that are wa-ter soluble and not volatile. The three principal processes that determine the urinary excretion of a drug are glomerular filtration, tubular secretion, and tubular reab-sorption (mostly passive back-diffusion). Active tubular reabsorption also may have some influence on the rate of excretion for a limited number of compounds.
The ultrastructure of the glomerular capillary wall is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights. This selective filtration is im-portant in that it prevents the filtration of plasma pro-teins (e.g., albumin) that are important for maintaining an osmotic gradient in the vasculature and thus plasma volume.
Several factors, including molecular size, charge, and shape, influence the glomerular filtration of large mole-cules. The restricted passage of macromolecules can be thought of as a consequence of the presence of a glomerular capillary wall barrier with uniform pores.
Since approximately 130 mL of plasma water is filtered across the porous glomerular capillary membranes each minute (190 L/day), the kidney is admirably suited for its role in drug excretion. As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of the driving force provided by cardiac pumping.
All unbound drugs will be filtered as long as their mo-lecular size, charge, and shape are not excessively large. Compounds with an effective radius above 20 Å may have their rate of glomerular filtration restricted; hin-drance to passage increases progressively as the molecu-lar radius increases, and passage approaches zero when the compound radius becomes greater than about 42Å.
Charged substances (e.g., sulfated dextrans) are usu-ally filtered at slower rates than neutral compounds (e.g., neutral dextrans), even when their molecular sizes are comparable. The greater restriction to filtration of charged molecules, particularly anions, is probably due to an electrostatic interaction between the filtered molecule and the fixed negative charges within the glomerular capillary wall. These highly anionic struc-tural components of the wall contribute to an electro-static barrier and are most likely in the endothelial or glomerular basement membrane regions.
Molecular configuration also may influence the rate of glomerular filtration of drugs. Differences in the three-dimensional shape of macromolecules result in a restriction of glomerular passage of globular molecules (e.g., proteins) to a greater extent than of random coil or extended molecules (e.g., dextrans). Thus, the effi-cient retention of proteins within the circulation is at-tributed to a combination of factors, including their globular structure, their large molecular size, and the magnitude of their negative charge.
Factors that affect the glomerular filtration rate (GFR) also can influence the rate of drug clearance. For instance, inflammation of the glomerular capillaries may increase GFR and hence drug filtration. Most drugs are at least partially bound to plasma proteins, and therefore their actual filtration rates are less than the theoretical GFR. Anything that alters drug–protein binding, however, will change the drug filtration rate. The usual range of half-lives seen for most drugs that are cleared solely by glomerular filtration is 1 to 4 hours. However, considerably longer half-lives will be seen if extensive protein binding occurs.
Also, since water constitutes a larger percentage of the total body weight of the newborn than of individu-als in other age groups, the apparent volume of distri-bution of water-soluble drugs is greater in neonates. This results in a lower concentration of drug in the blood coming to the kidneys per unit of time and hence a decreased rate of drug clearance. The lower renal plasma flow in the newborn also may decrease the glomerular filtration of drugs.
An important determinant of the urinary excretion of drugs (i.e., weak electrolytes) is the extent to which sub-stances diffuse back across the tubular membranes and reenter the circulation. In general, the movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water that occurs throughout most portions of the nephron, which results in an increased concentration of drug in the luminal fluid. The concentration gradient thus established will facilitate movement of the drug out of the tubular lu-men, given that the lipid solubility and ionization of the drug are appropriate.
The pH of the urine (usually between 4.5 and 8) can markedly affect the rate of passive back-diffusion. Theback-diffusion occurs primarily in the distal tubules and collecting ducts, where most of the urine acidification takes place. Since it is the un-ionized form of the drug that diffuses from the tubular fluid across the tubular cells into the blood, it follows that acidification in-creases reabsorption (or decreases elimination) of weak acids, such as salicylates, and decreases reabsorption (or promotes elimination) of weak bases, such as ampheta-mines. However, should the un-ionized form of the drug not have sufficient lipid solubility, urinary pH changes will have little influence on urinary drug excretion.
Effects of pH on urinary drug elimination may have important applications in medical practice, especially in cases of overdose. For example, one can enhance the elimination of a barbiturate (a weak acid) by adminis-tering bicarbonate to the patient. This procedure alka-linizes the urine and thus promotes the excretion of the now more completely ionized drug. The excretion of bases can be increased by making the urine more acidic through the use of an acidifying salt, such as ammonium chloride.
A number of drugs can serve as substrates for the two active secretory systems in the proximal tubule cells. These transport systems, which actively transfer drugs from blood to luminal fluid, are independent of each other; one secretes organic anions (Figure 4.3), and the other secretes organic cations. One drug substrate can compete for transport with a simultaneously adminis-tered or endogenous similarly charged compound; this competition will decrease the overall rate of excretion of each substance. The secretory capacity of both the or-ganic anion and organic cation secretory systems can be saturated at high drug concentrations. Each drug will have its own characteristic maximum rate of secretion (transport maximum, Tm).
Some drugs that are not candidates for active tubu-lar secretion may be metabolized to compounds that are. This is often true for metabolites that are formed as a result of conjugative reactions. Because the conju-gates are generally not pharmacologically active, in-creases in their rate of elimination through active secre-tion usually have little effect on the drug’s overall duration of action.
These active secretory systems are important in drug excretion because charged anions and cations are often strongly bound to plasma proteins and therefore are not readily available for excretion by filtration. However, since the protein binding is usually reversible, the active secretory systems can rapidly and efficiently remove many protein-bound drugs from the blood and transport them into tubular fluid.
Any drug known to be largely excreted by the kid-ney that has a body half-life of less than 2 hours is prob-ably eliminated, at least in part, by tubular secretion. Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron. Several pharmacologically active drugs, both anions and cations, known to be secreted are listed in Table 4.5.
It is important to appreciate that these tubular transport mechanisms are not as well developed in the neonate as in the adult. In addition, their functional ca-pacity may be diminished in the elderly. Thus, com-pounds normally eliminated by tubular secretion will be excreted more slowly in the very young and in the older adult. This age dependence of the rate of renal drug se-cretion may have important therapeutic implications and must be considered by the physician who prescribes drugs for these age groups.
Finally, compounds that undergo active tubular se-cretion also are filtered at the glomerulus (assuming protein binding is minimal). Hence, a reduction in se-cretory activity does not reduce the excretory process to zero but rather to a level that approximates the glomerular filtration rate.
Some substances filtered at the glomerulus are reab-sorbed by active transport systems found primarily in the proximal tubules. Active reabsorption is particularly important for endogenous substances, such as ions, glucose, and amino acids (Fig. 4.4), although a small number of drugs also may be actively reabsorbed. The probable location of the active transport system is on the luminal side of the proximal cell membrane. Bidirectional active transport across the proximal tubule also occurs for some compounds; that is, a drug may be both actively reabsorbed and secreted. The oc-currence of such bidirectional active transport mecha-nisms across the proximal tubule has been described for several organic anions, including the naturally occurring uric acid . The major portion of filtered urate is probably reabsorbed, whereas that eventually found in the urine is mostly derived from active tubular secretion.
Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfin-pyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A com-plicating observation is that a drug may primarily in-hibit active reabsorption at one dose and active secre-tion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate excretion, while high doses have a uricosuric effect.
This is offered as an explanation for the apparently paradoxi-cal effects of low and high doses of drugs on the total excretory pattern of compounds that are handled by re-nal active transport.
The rate of urinary drug excretion will depend on the drug’s volume of distribution, its degree of protein bind-ing, and the following renal factors:
Glomerular filtration rate
· Tubular fluid pH
· Extent of back-diffusion of the unionized form
· Extent of active tubular secretion of the com-pound
· Possibly, extent of active tubular reabsorption
Changes in any of these factors may result in clini-cally 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 ef-fect 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 inter-val, reduction in the maintenance dose, or both) be-comes 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.
The liver secretes about 1 L of bile daily. Bile flow and composition depend on the secretory activity of the he-patic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composi-tion 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 diffu-sion. 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 ra-tio 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 com-pounds 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 an-ions, 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 trans-ported 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 proxi-mal 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 se-creted drugs generally do not recycle, because they are not substrates for the intestinal bile acid transport sys-tem, and they are generally too highly charged to back-diffuse 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 un-dergoes metabolic changes in the liver, is excreted by the kidneys, or both. This process permits the conserva-tion 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 re-sponsible for a drug’s long persistence in the body. Orally administered activated charcoal and/or anion ex-change resins have been used clinically to interrupt en-terohepatic cycling and trap drugs in the gastrointesti-nal tract.
As stated earlier, many foreign compounds are ei-ther partially or extensively metabolized in the liver.
Conjugation of a compound or its metabolites is espe-cially important in determining whether the drug will undergo biliary excretion. Frequently, when a com-pound is secreted into the intestine through the bile, it is in the form of a conjugate. Conjugation generally en-hances 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 reab-sorbed readily from the gastrointestinal tract unless the conjugate is hydrolyzed by gut enzymes such as β-glucuronidase. Chloramphenicol glucuronide, for ex-ample, 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 ac-tively transporting the same organic anion substrates. However, the two organs have certain quantitative dif-ferences in drug affinity for the transporters. It has been suggested that several subsystems of organic anion trans-port 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 demon-strated at both ends of the age continuum. For example, ouabain, an unmetabolized cardiac glycoside that is se-creted into the bile, is particularly toxic in the newborn. This is largely due to a reduced ability of biliary secre-tion to remove ouabain from the plasma.
Increases in hepatic excretory function also may take place. After the chronic administration of either pheno-barbital or the potassium-sparing diuretic spirono- lactone, the rate of bile flow is augmented. Such an in-crease in bile secretion can reduce blood levels of drugs that depend on biliary elimination.
Finally, the administration of one drug may influ-ence the rate of biliary excretion of a second coadmin-istered 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 intes-tinal 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 re-circulation.