Answer to Practice Problem #5 Dose- and Time-Dependent Pharmacokinetics Tutorial:

 

 

 

A drug that exhibits a high first-pass effect is one that exhibits a high intrinsic hepatic clearance. At low doses, before saturation of the enzymes occurs, as you increase the oral dose, the AUC will increase proportionally. As the oral dose is continues to be increased and the metabolizing enzymes become saturated, the fraction escaping first-pass metabolism will increase (i.e., systemic availability increases). At this point in time, the increase in AUC_oral will be greater than the increase in dose (e.g., a doubling of dose will result in more than a doubling of the AUC_oral). Notice for the AUC_iv that for a given dose the intravenous AUC is greater than the oral AUC … because drug administered iv is not subjected to first pass metabolism. Hence, as the dose increases, the AUC will increase proportionally. To consider this mathematically, remember that

 

AUC_oral = D_oral/(f_ubCL_uint)

 

As enzymes become saturated, the CL_uint decreases. Hence, the AUC_oral will increase disproportionately to the dose. A doubling of dose will cause more than a doubling of the AUC_oral. On the other hand, for a high clearance drug

 

AUC_iv = D_iv/CL_H ~ D_iv/Q_H

 

Hence, increasing the dose will result in a proportional increase in the AUC after intravenous administration.

 

 

 

Last revised 07/14/05

 

ã 2005 -  Craig K. Svensson, Pharm.D., Ph.D.

 

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