Expanded Answers for Study Problems in: Rowland & Tozer's Clinical Pharmacokinetics: Concepts and Applications

Chapter 11 - Basic Considerations

Study Problems on Page 181-182

1. In order to determine the mechanism of renal elimination of these compounds, you must compare the CL_R to the f_uGFR. For theophylline, with a f_u = 0.50 and GFR = 120 mL/min, the clearance if the drug were only filtered would be 60 mL/min. Since the value for CL_R (10 mL/min) is less than the value for f_uGFR, the drug must undergo filtration and reabsorption.

For phenytoin,  f_uGFR = 12 mL/min. Therfore, if the drug were only filtered the renal clearance would be 12 mL/min. Since the value is less than this, we know the drug is filtered and reabsorbed. Moreover, since the renal clearance is equal to the product of f_u and urine flow, we know the drug must be in equilibrium with free drug in plasma.

For cefonicid,  f_uGFR = 2.4 mL/min. Since the renal clearance value exceeds this, the drug must undergo filtration and active tubular secretion.

2.

a) The question is asking for those conditions wherein the renal clearance of a weak acid will be sensitive to changes in urine pH. This excludes condition #1, since only passive tubular reabsorption is sensitive to pH changes and a drug which is polar will not be reabsorbed (it has to have the appropriate lipophilicty to cross the tubular membrane). Condition #2 is consistent, since a weak acid with a pKa of 5.0 would be in the range in which you would expect changes in pH to result in changes in ionization. Condition #3 is not relevant to the parameter of interest. Volume of distribution does not impact clearance, renal or otherwise. Condition #4 does not really indicate the probability that the renal clearance will be sensitive to changes in urine pH. The fraction of the drug excreted unchanged simply provides with the contribution of renal elimination to the overall elimination of the drug.

b) Condition #1 is not correct. A drug which is polar is not going to be reabsorbed, therefore, forced diuresis will not enhance its elimination. Condition #2 is correct. Forced diuresis decreases the concentration gradient and decreases tubular reabsorption. Since the fraction of the drug eliminated unchanged exceeds 50%, an increase in the renal clearance may have a significant impact on the elimination kinetics of the drug. Condition #3 is not correct. A polar drug will not be reabsorbed and, therefore, renal clearance will not be enhanced through forced diuresis. Condition #4 is not correct. Since the ratio of unbound clearance to creatinine clearance is 1.0, the drug is either secreted and reabsorbed to exactly the same extent (an unlikely occurrence), or it is only filtered. Since you are told that the drug is not secreted, you know that only filtration is taking place. Hence, forced diuresis will not alter the elimination of this drug.

c) Condition #1 is correct. Since the renal clearance for this drug well exceeds the GFR, it is clear that ATS must take place. Condition #2 is incorrect. If the renal extraction ratio were 0.1, this drug would be a low clearance drug. Its high renal clearance value indicates that is not the case. In fact, extraction can be calculated directly (as shown in the answers in the book)using the relationship:

Q_RB x E = CL_R

Condition #3 is uncertain. The data given does not allow you to calculate the fraction of drug excreted renally. Condition #4 is also uncertain. The renal clearance value alone tells you nothing about the degree of plasma protein binding.

d) Condition #1 is incorrect. Simply knowing the value of renal clearance tells one nothing about the stability of this excretion. Condition #2 is also incorrect. For a drug which is reabsorbed, the renal clearance will actually increase as you increase urine flow. Condition #3 is correct. Remember that clearance is excretion rate divided by concentration. Thus, if a constant fraction is reaborbed, the excretion rate will be proportional plasma concentration and renal clearance will remain constant with time.

3. a) Alcohol is readily absorbed from the tubule and is non-ionizable. Therefore, the concentration of alcohol in the urine is in equilibrium with the free alcohol concentration in blood. Since alcohol is not bound to components is blood, this means the urine alcohol concentration should be approximately the same as the blood alcohol.

4a)

1. Only a drug which is reabsorbed and is ionizable in the range of adjustable urine pH will exhibit a renal clearance which changes with changes in urine pH. Nafcillin is a polar compound and, therefore, is not reabsorbed. Tocainide is a non-polar, basic drug which is ionizable in the range of adjustable urine pH. Cyclosporine is not ionizable, and therefore, its reabsorption (and renal clearance) is not altered by changes in urine pH.

2. For each drug you are provided with the volume of distribution and half-life. From these values you can calculate the total clearance for each drug. In addition, you are given the fraction of drug excreted unchanged (f_e). This value times the total clearance provides the renal clearance.If you make these calculations it is very easy to see that the renal clearance of nafcillin is larger than that of tocainide or cyclosporine.

3. Remember that polar compounds pass across the placental membrane poorly. Therefore, nafcillin will exhibit the poorest passage across the placenta.

4. Forced diuresis decreases the concentration gradient driving drug from the tubules back into the blood. Thus, forced diuresis is useful in a drug that undergoes tubular reabsorption. If one compares that calculated renal clearance for each drug with the f_uGFR, you will find that tocainide exhibits significant tubular reabsorption (the renal clearance is 1.46 L/hr, while the f_uGFR = 6.8 L/hr). Naficillin, as a polar molecule, is not reabsorbed. For cyclosporine, renal elimination is a relatively minor pathway of elimination.Therefore, only for tocainide would forced diuresis be useful in a drug overdose.

5. After an identitical dose, the drug with the smallest volume of distribution will exhibit the highest peak concentration.

6. Again, CL can be calculated easily since the volume of distribution and half-life are given.All one needs to do is calculate the CL for each drug and compare the values.

4.b)

1. Nafcillin will exhibit an increase in CL_R if it is a low intrinsic clearance drug, i.e., it will exhibit restrictive clearance. On the other hand, if it is a high intrinsic clearance drug, it will exhibit non-restrictive clearance; which means the CL_R will not change with changes in protein binding. To determine if the drug is a low or high intrinsic clearance drug, we must compare the CL_R to the renal plasma flow (because a high intrinsic clearance drug will have a CL_R which approximates renal plasma flow). If you calculate the CL_R of nafcillin you will find it to be considerably less than renal plasma flow. Therefore, this drug is a low intrinsic clearance drug and the CL_R will increase with a displacement of drug from protein binding sites.

2. Renal clearance will be decreased when less of the drug is ionized and more can be reabsorbed. As tocainide is the only drug of the three that exhibits pH-dependent reabsorption, we only need to be concerned with this drug. As a weak base, the drug will be more highly unionized at alkaline pH, Therefore, alkalinization of urine should decrease the renal clearance of this compound.

3. For nafcillin to be evenly distributed throughout extracellular fluids evenly it would have to exhibit no protein binding an have a volume of distribution of 15 L.

4. Since the fraction of cyclosporine excreted unchanged is <0.01, >metabolism is obviously the primary route of elimination for this drug.

5. As discussed in previous sections, having a high degree of protein binding does not mean the volume of distribution for the drug is low.

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