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

Chapter 22 - Dose and Time Dependencies

Study Problems on Page 418-423

4.a) Recognizing that

CL/F = Do/AUC_o ,

we can calculate CL/F for each dose (Table 22-8)

Clearly, as the dose is increased, either CL is decreasing or F is increasing. I or III would result in a decrease in clearance with increasing dose, while VI would result in an increase in F with increasing dose. Thus, I, III or VI are possible explanations for the dose-dependency displayed in this data.

b) With steady-state plasma concentration and infusion rate we can calculate CL. The CL at infusion rates of 5, 10 and 15 are 2.5, 1.5 and 1.1 L/hr, repsectively. Again, as dosing rate is increased, the CL of the drug decreases. Thus, both I and III are possible explanations for the data. VI is not a viable possibility since the drug is given by intravenous infusion.

c) Again, we can calculate the CL at different doses, but with initial concentration data we can also calculate the V_d.

While the CL of the drug is decreasing, the V_d remains essentially unchanged. This indicates that I and III are possible explanations for this data.

5. Remember that renal clearance will change as a function of dose only when a carrier-mediated renal excretory process is involved or plasma protein binding is dose- or concentration-dependent. There are two carrier-mediated renal excretory processes: active tubular secretion and active tubular reabsorption. Glucose is not bound to plasma proteins, so we can exclude that explanation. Since renal clearance increases as the concentration increases, glucose must undergo active tubular reabsorption. As plasma glucose concentration increases, the amount filtered increases; resulting in an increased glucose concentration in the renal tubules. When this saturates the carriers for reabsorption, more glucose will be excreted in the urine; hence, the increased renal clearance (which you can determine by dividing the ER by the glucose concentration). This concentration-dependent renal excretion is one reason there has been a move away from urine glucose measurements in monitoring diabetics.

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