organic acids and bases occurs only in the proximal segment.
between the urine and plasma, and some salicylic acid diffuses back into the blood.
Acidification of the urine depresses the ionization of salicylic acid, since
Thus the increase in H+ concentration drives the equilibrium to the side of undissociated salicylic acid, thereby increasing the fraction of the more lipid-soluble, nonionized form.
The higher concentration gradient of the undissociated species favors more rapid reabsorption, and consequently the rate of salicylic acid excretion is reduced. Conversely, an alkaline urine promotes the urinary excretion of salicylic acid. In fact, practical use is made of these effects of pH on drug excretion in the treatment of poisoning with certain weak acids, such as aspirin or phenobarbital. Sodium bicarbonate may be administered in order to produce an alkaline urine and hasten elimination of the drug (cf. p. 359).
Conversely, for weak bases, such as cocaine, an alkaline urine retards excretion and an acidic urine formed by the administration of ammonium chloride enhances urinary elimination.
TUBULAR SECRETION. Whereas active reabsorption plays a significant part in the conservation of many essential endogenous compounds like glucose, carrier-mediated processes account for the reabsorption of only small quantities of a few drugs or nonessential substances. In contrast, the mechanisms responsible for active tubular secretion of organic compounds are of lesser consequence in the normal formation of urine, but are important processes for the excretion of a number of drugs and drug metabolites. The epithelial cells of the proximal tubules contain transport proteins that are inserted into the plasma membranes on the vascular (basolateral) and luminal (apical) side of the cells. These carriers bind drugs and facilitate their transport across the plasma membrane. Three major types of transporters have been identified in the proximal tubule and are expressed in other tissues as well. Two of these, the organic anion transporters (OAT) and the organic cation transporters (OCT) are named for their substrates. The third type, the multi-drug resistant (MDR) gene product or p-glycoprotein, derives its name from its first identification in tumor cells.
Examples of substrates for the organic anion transporters include a variety of acidic drugs such as penicillin and salicylic acid, and acidic drug metabolites such as glucuronide conjugates. The acid para-aminohippuric acid (PAH) is secreted so rapidly
by this carrier type that it is entirely removed from the plasma in a single pass through the kidney. The substrates for the organic cation transporters include quaternary ammonium compounds. And the substrates for the multi-drug resistant transporters include both neutral and cationic compounds such as digoxin and quinolone antibiotics (Table 7–3).
There are limits to the capacity of these carrier mechanisms to actively secrete compounds from the blood into the urine. In addition, drugs may bind to the same carrier, share the same transport process, and compete with each other for binding sites on the same carrier. Consequently, when multiple compounds that share the same transport process are present in the blood coming to the tubule, one compound may inhibit the secretion of another. If the total quantity of drug or drug metabolite to be secreted is in excess of available carrier, the rates of secretion of the individual compounds will be decreased compared with their rates in the absence of each other. For example, the agent probenecid, used in the treatment of gout, binds avidly to the organic anion transporter and blocks the tubular secretion of penicillin. When penicillin was in short supply during the period after its introduction into therapeutics, co-administration of probenecid was used as an effective method for prolonging retention of the antibiotic in the body by blocking its tubular secretion.
The extent to which a drug or drug metabolite is eliminated in the urine following tubular secretion is dependent on the degree of its ionization within the tubular urine.
Secretion of the quaternary ammonium compounds is tantamount to urinary elimination, since these agents are fully ionized regardless of the pH of the urine. Organic acids, such as penicillin, also are highly ionized in the urine and therefore undergo little reabsorption.
RATE OF DRUG EXCRETION. The rate at which a drug will be eliminated in the urine is the net result of the three renal processes: glomerular filtration, tubular secretion, and tubular reabsorption. The rates of glomerular filtration and tubular secretion are dependent on the rate at which a drug is presented to the kidney—on its concentration in plasma. The rate of reabsorption by the tubules is dependent on the concentration of drug in the urine. For glomerular filtration, it is the concentration of free drug in the plasma that is important, since protein-bound drug cannot be filtered. On the other hand, the extent of protein binding, as long as it is reversible, makes little difference in the rate of elimination of those agents that can be actively transported out of the renal tubular cell.
The fraction of drug that is bound in plasma is in equilibrium with the fraction of drug that is free. As the latter is removed by secretion, the protein-drug complex dissociates, and more free drug becomes available to the active secretory process. Thus it is the concentration of both free and bound drug in plasma that is important in determining the rate of tubular secretion.
Determinations of the rates at which certain drugs are excreted by the kidney have proven to be useful procedures for diagnosing the functional status of this organ. For example, if we wish to assess the competence of the glomeruli, we need a means of measuring the volume of plasma that the glomeruli are capable of filtering in a given period. A simple way of obtaining this information is to determine the rate at which a foreign compound present in the plasma appears in the urine. The compound used as a yardstick of glomerular competence would have to satisfy the following requirements: (1) it must be freely filterable in the glomeruli, i.e. it must not be bound to plasma protein;
(2) it must be neither reabsorbed nor actively secreted into the tubular urine; (3) it must be nontoxic and have no direct or indirect pharmacologic effect on renal function; (4) it
must remain chemically unaltered during its passage through the kidney; and (5) it must be a chemical the concentration of which can be accurately determined in both urine and plasma. The polymeric carbohydrate inulin meets all these requirements. It is freely filterable by the glomeruli; it can reach the urine only by glomerular filtration; all the inulin filtered is excreted, since it is not reabsorbed in its passage through the tubules; and methods are available for its quantitative determination in body fluids. Therefore, following inulin administration, the amount recovered in the urine in a given interval is equal to the amount filtered by the glomeruli in that same period. For example, if 10mg is the amount of inulin recovered in the voided urine in 10 minutes, then inulin is being filtered in the glomeruli at the rate of 1mg/minute.
The next question we need to answer in order to determine the efficiency of the glomeruli is, ‘How many milliliters—what volume—of plasma have to be filtered each minute to yield the amount recovered per minute in the urine?’ The answer can be obtained very easily by taking a sample of blood during the time the urine is being collected and determining how much inulin is present per milliliter of plasma. If we find the plasma concentration to be 0.008mg/ml, then 125ml of plasma must be filtered each minute to provide the 1mg excreted by the kidney per minute:
(Equation1)
Quantitative data on kidney function obtained in this manner are termed a renal plasma clearance study. Renal plasma clearance is defined as the volume of plasma needed to supply the amount of a specific substance excreted in the urine in 1 minute. A substance like inulin, which not only is completely filterable but is neither reabsorbed nor secreted by the tubular cells, has a renal plasma clearance identical to the rate at which it is filtered by the glomeruli. Thus the clearance of a substance such as inulin measures the glomerular filtration rate (GFR), expressed in milliliters per minute. In a healthy 70-kg adult male the average GFR is about 130ml/min, indicating that 130ml of plasma are filtered by the glomeruli each minute. This value was established using the procedures just described; similar procedures are used clinically to assess glomerular function in patients.
Renal plasma clearance (ClR) is usually calculated as follows:
(Equation2) where U is the concentration of the test substance per milliliter of urine, V is the volume of urine excreted per minute and P is the concentration of test substance per milliliter of plasma. In our example above, the volume of urine collected in 10 minutes was 10ml.
Thus V=1ml/min and U=10mg/10ml, or 1mg/ml. Then:
Whereas Equations 1 and 2 are mathematically identical, the latter indicates not only the functional capacity of the glomeruli but also the kidney’s ability to concentrate urine by removal of water. Comparison of the milliliters of plasma cleared with the milliliters of urine voided in 1 minute yields direct information of the amount of water reabsorbed during passage through the tubule. In our example, 124ml of each 125ml filtered was absorbed. And simple arithmetic shows that continued excretion at the rate of 1ml per minute will lead to a daily output of urine of 1440ml.
Certain organic acids, such as para-aminohippuric acid (PAH), are secreted so rapidly and efficiently by the renal epithelium that they are almost entirely removed from the plasma in a single passage through the kidney. (Obviously, this can occur only when the plasma levels are low enough to ensure that the carrier transport system is not overloaded.) These acids are also not reabsorbed to any significant degree. A substance like PAH can then be used in clearance studies to obtain information about the total amount of plasma flowing through the kidneys in a stated unit of time. The term clearance is used here to mean exactly what it did in the case of the clearance of inulin:
the amount of plasma needed to supply the amount of a specific substance excreted in the urine in 1 minute. Then, if the kidneys extract all of a compound that is delivered to them by the blood during a single passage, the clearance of that substance is equal to the volume of plasma flowing through the kidneys per minute. By measuring the concentration of PAH per milliliter of urine (U), the volume of urine excreted per minute (V) and the concentration of PAH per milliliter of plasma (P), and then applying Equation 2, we obtain the renal clearance of PAH in milliliters per minute. This clearance of PAH represents the rate of plasma flow through the kidneys. The average renal plasma flow in a healthy 70-kg adult male is about 650ml/min.
The determination of the renal plasma clearance of any drug can give some insight into the mechanisms by which the drug is excreted when this clearance is compared with the normal glomerular filtration rate, i.e. 130ml/min as obtained with inulin. If the concentration of drug not bound to plasma proteins is used to calculate its renal plasma clearance, an expression of the excretion ratio is obtained:
A ratio of less than 1 indicates that the drug is filtered, perhaps also secreted, and then partially reabsorbed. A substance such as glucose has an excretion ratio of zero since it is completely reabsorbed in the healthy individual. A value greater than 1 indicates that secretion, in addition to filtration, is involved in the excretion. Obviously, the greatest excretion ratio, about 5, would be obtained with a substance like PAH.