Chapter 16 Routes of Excretion

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Renal Excretion

The major organ for the excretion of drugs is the KIDNEY. The functional unit of the kidney is the nephron and components of the nephron include Bowman's capsule, Proximal Tubule, Loop of Henle, Distal Tubule and the Collecting Duct. Low molecular weight molecules are filtered in Bowman's capsule. Active secretion of weak electrolyte drugs (acids) and reabsorption of water occurs in the proximal tubules. Additional reabsorption of water occurs in the Loop of Henle. Passive reabsorption of water and lipid soluble drugs occur in the distal tubule.

There are three major renal excretion processes to consider; 1) glomerular filtration; 2) tubular secretion; and 3) tubular re-absorption

Figure 16.2.1 One Nephron of the Kidney

Glomerular Filtration

In the glomerular all molecules of low molecular weight (< 60,000 Dalton) are filtered out of the blood. Most drugs are readily filtered from the blood unless they are tightly bound to large molecules such as plasma protein or have been incorporated into red blood cells. The glomerular filtration rate varies from individual to individual but in healthy individuals the normal range is 110 to 130 ml/min (≈ 180 L/day). About 10% of the blood which enters the glomerular is filtered. This filtration rate is often measured by determining the renal clearance of inulin. Inulin is readily filtered in the glomerular, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to the glomerular filtration rate.

Again, most drugs are filtered from blood in the glomerular, the overall renal excretion however is controlled by what happens in the tubules. More than 90% of the filtrate is reabsorbed. 120 ml/min is 173 L/day. Normal urine output as you may realize is much less than this, about 1 to 2 liter per day.

Tubular secretion

In the proximal tubule there is re-absorption of water and active secretion of some weak electrolyte but especially weak acids. As this process is an active secretion it requires a carrier and a supply of energy. This may be a significant pathway for some compounds such as penicillins. Because tubular secretion is an active process there may be competitive inhibition of the secretion of one compound by another. A common example of this phenomena is the inhibition of penicillin excretion by competition with probenecid. When penicillin was first used it was expensive and in short supply, thus probenecid was used to reduce the excretion of the penicillin and thereby prolong penicillin plasma concentrations (PDR). Since then it has been shown that probenecid also alters the distribution of penicillins to various tissues causing more drug to distribute out of plasma, causing even less to be eliminated. This could also be used to reduce the excretion of cephalosporins.

Drugs or compounds which are extensively secreted, such as p-aminohippuric acid (PAH), may have clearance values approaching the renal plasma flow rate of 425 to 650 ml/min, and are used clinically to measure this physiological parameter (see Documenta Geigy).

Tubular re-absorption

In the distal tubule there is passive excretion and re-absorption of lipid soluble drugs. Drugs which are present in the glomerular filtrate can be reabsorbed in the tubules. The membrane is readily permeable to lipids so filtered lipid soluble substances are extensively reabsorbed. A reason for this is that much of the water, in the filtrate, has been reabsorbed and therefore the concentration gradient is now in the direction of re-absorption. Thus if a drug is non-ionized or in the unionized form it maybe readily reabsorbed.

Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption for many drugs. When urine is acidic weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed. Making the urine more acidic can cause less reabsorption of weak bases or enhanced excretion. These changes can be quite significant as urine pH can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or drugs (which can increase or decrease urine pH).

In the case of a drug overdose it is possible to increase the excretion of some drugs by suitable adjustment of urine pH. For example, in the case of pentobarbital (a weak acid) overdose it may be possible to increase drug excretion by making the urine more alkaline with sodium bicarbonate injection.

Figure 16.2.2 Pentobarbital Ionization

This method is quite effective if the drug is extensively excreted as the unchanged drug (i.e. fe approaches 1). If the drug is extensively metabolized then alteration of kidney excretion will not alter the overall drug metabolism all that much.

The effect of pH change on tubular re-absorption can be predicted by consideration of drug pKa according to the Henderson-Hesselbalch equation.

Renal clearance

One method of quantitatively describing the renal excretion of drugs is by means of the renal clearance value for the drug. Renal clearance relates the rate of excretion, Δ U/Δ t, to drug concentration. Units are ml/min.

Equation 16.2.1 Rate of Excretion

Remember that renal clearance can be calculated as part of the total body clearance for a particular drug. Renal clearance can be used to investigate the mechanism of drug excretion. If the drug is filtered but not secreted or reabsorbed the renal clearance will be about 120 ml/min in normal subjects. If the renal clearance is less than 120 ml/min then we can assume that at least two processes are in operation, glomerular filtration and tubular re-absorption. If the renal clearance is greater than 120 ml/min then tubular secretion must be contributing to the elimination process. It is also possible that all three processes are occurring simultaneously. The drug renal clearance value can be compared with physiologically significant values, e.g. glomerular filtration rate (GFR) of approximately 120 ml/min or renal plasma flow of about 650 ml/min.

Renal clearance is then:

Equation 16.2.2 Renal Clearance

Each of these rates can be explored further in terms of fraction unbound (f_U), GFR, renal blood flow (Q_R), intrinsic secretion clearance (CLⁱ_sec) and fraction reabsorbed (f_R).

Equation 16.2.3 Renal clearance expanded (Bauer, p 14)

The influence of f_U, GFR, (CLⁱ_sec and f_R can be explored using the interactive graph to calculate plasma concentrations after iv bolus or oral dosing.

Renal clearance values can range from 0 ml/min, the normal value for glucose which is usually completely reabsorbed to a value equal to the renal plasma flow of about 650 ml/min for compounds like p-aminohippuric acid.

We can calculate renal clearance using the pharmacokinetic parameters ke and V. Thus CL_renal = ke • V. Renal clearance can also be determined as U^∞/AUC. We can calculate renal clearance by measuring the total amount of drug excreted over some time interval and dividing by the plasma concentration measured at the midpoint of the time interval. (This was part of a laboratory experiments -- first beaker experiment).

Equation 16.2.4 Renal Clearance

Equation 16.2.5 Renal Clearance

To continue we can briefly look at some other routes of drug excretion. We will then return to the topic of renal excretion by considering drug dosage adjustments in patients with reduced renal function.

References

Bauer, L.A. 2008 Applied Pharmacokinetics, Second Edition, McGraw-Hill, New York, NY
The Kidney at Wikipedia

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