Inappropriate use of the law of corresponding areas to calculate the time course of absorption for multicompartmental systems

From the law of corresponding areas, Dost has derived a simple method for calculating the percentage absorbed of a drug during an entire period of treatment. The method utilizes a graphical procedure to determine the fraction of a dose absorbed at each time point, when data are available following oral and intravenous administration of the drug. The method has been suggested for use with drugs whose kinetics are described by single and multicompartment systems. The method is valid for single-compartment body systems and can be shown to be the graphical equivalent of the well-known Wagner-Nelson method. However, it can be proved mathematically that the graphical method will not yield correct answers for multicompartment body systems. Here, for identical plasma concentrations following oral and intravenous administration of the same dose, the amount of drug in the peripheral compartment(s) will always be greater following intravenous administration than after oral administration (during the absorption phase). Therefore, areas under the curve calculated from shifted intravenous curves will always overestimate the amount absorbed. Analog and digital computer simulations illustrate the mathematical treatments.Supported in part by Grant GM 16496 from the National Institutes of Health.Presented in part at the Sixth International Congress of Pharmacology, IUPHAR, July 20–25, 1975, Helsinki, Finland.This paper was submitted to a Consulting Editor who served as a Journal Editor during its review process.During the course of this study, Dr. Galeazzi was a Fellow of the Swiss National Science Fund.