First-pass metabolism commonly is determined from the difference in the area under the blood concentration time curve (AUC) that is observed with oral versus intravenous administration of a compound. It is not fully appreciated that this technique serves as an accurate indicator of first-pass metabolism only when the clearance of the compound under consideration is first order (unsaturated) throughout the range of blood concentrations observed in the study. For example, multiple publications continue to mistakenly use AUC measurements to assess the first-pass metabolism of ethanol, a compound cleared primarily via zero-order kinetics. This report briefly reviews the physiologic basis of measurements of first-pass metabolism, demonstrates the errors that result from application of this technique when clearance is not first order, and, using ethanol as an example, describes a technique that can be used to measure first-pass metabolism when clearance deviates from first order.
Bibliographical noteFunding Information:
Supported in part by the Department of Veterans Affairs; by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK 13309-25; by the Research Service, Minneapolis Veterans Affairs Medical Center (M.D.L.); and by the Department of Physiology, University of Minnesota (D.G.L.).