Expanded Answers for Study Problems in: Rowland & Tozer's Clinical Pharmacokinetics: Concepts and Applications, 3rd edition.

Chapter 17 - Interacting Drugs

Study Problems on Page 284-286

2.a) When f_u is increased for a low clearance drug, the CL will also increase. Since

C_ss = Ko/CL = Ko/f_uCL_uint

an increase in CL will cause a decrease in the steady-state concentration. An increase in f_u will also result in an increase in the volume of distribution. Since clearance and volume change proportionately, the half-life will remain unchanged. This means that the time required to reached steady-state after initiation of the infusion will remain the same. This is depicted in the graph (II-7) on p. 540.

b) A decrease in the CL_int will cause an increase in the steady-state concentration as depicted. But since the clearance decreases while the volume of distribution remain unchanged, the half-life will increase. This results in an increase in the time required to achieve steady-state; as depicted in the graph (II-8) on p. 540.

3. a) The plot is shown in the answer in the back of the text and will not be reproduced here.Completion of the table is very straightforward. Since,

V_d = D_iv/C₀

we can calculate V_d for chlrodiazepoxide with and without ketoconazole. From Table 17.4, it is obvious that C₀ does not change, and since the dose is the same in both cases, V_d obviously does not change. To calculate CL, remember that

CL = kV_d

Also,

t_1/2 = 0.693/k

This will yield a CL of 1.63 L/hr without ketoconazole and 0.90 L/hr with ketoconazole.

To determine the mechanism of this decreased clearance, we have to first determine whether this is a low of high intrinsic clearance drug. Since the normal hepatic blood flow is 1.0 to 1.5 L/min, the clearance of this drug (note, you must convert to L/min to compare with hepatic blood flow) is much less than hepatic blood flow and, therefore, must be a low intrinsic clearance drug. The clearance values in the back of the book appear to be in error. The clearance for the drug without ketoconazole is 0.65 L/hr, while that with ketoconazole is 0.36 L/hr. Recall that the hepatic clearance of a low intrinsic clearance drug is a function of the fraction unbound in blood and the unbound intrinsic clearance. However, since the volume of distribution did not change, the fraction unbound must remain the same. Therefore, it appears that ketoconazole decreases the unbound intrinsic clearance.

5.a) As described in class, the renal clearance can be determined as:

Cl_R = ER_ss/C_ss

Since the CL_R without B present exceeds f_uGFR, the drug is clearly secreted. Moreover, CL_R with B is less than f_uGFR, indicating the drug is also reabsorbed.

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