Answer to Practice Problem #7 Dose- and Time-Dependent Pharmacokinetics Tutorial:
From the fact that amitriptyline is a basic, lipophilic drug, indicates that it binds to alpha1-acid glycoprotein. The average pharmacokinetic values indicates that binding is extensive. Additionally, the average Vss exceeds plasma volume (~3 L). This is important to recognize, since if the volume of distribution were equal to plasma volume, it would indicate that unbound drug does not distribute outside vascular space and changes in binding would not alter its distribution. However, the volume of distribution provided indicates the drug exhibits extensive tissue binding in addition the extensive plasma protein binding. Therefore, changes in plasma protein binding would disturb the equilibrium between the drug in tissue and that in plasma, resulting in changes in the volume of distribution. Remember that
Vss = Vp + (fup/fut)VT
If amitriptyline concentration increases with time, this would result in a decrease in the fup. A decrease in this value, while holding all other variables constant, will result in a decrease in the Vss. Thus, the graph of the relationship between Vss and time will look like this:
The next step in this problem would be to determine what happens to the clearance of the drug. You are told that CLT = 15 ml/min/kg. Additionally, very little drug is eliminated renally – meaning the total clearance is essentially equal to the hepatic clearance. In a normal 70 kg individual
CLT = 15 ml/min/kg x 70 kg = 1050 mL/min
This value is in the range of normal hepatic blood flow, suggesting this drug is perfusion rate-limited. Thus, the clearance will be independent of protein binding changes. Thus, the relationship between CLT and time is given as
Last revised 07/14/05
ã 2005 -
Craig K. Svensson, Pharm.D., Ph.D.
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