Noncompartmental area under the curve determinations for drugs that cycle in the bile

Drugs that are involved in the enterohepatic circulation (EHC) generally exhibit complex disposition profiles and are difficult to describe by classical methods. A noncompartmental method for calculating the area under the curve from time zero to time infinity (AUC) for substances that are involved the EHC is developed and tested. Previous methods have been based on specific compartmental models and/or have been limited to a single enterohepatic cycle. The current method uses the following equations: (formula; see text) for an IV dose or (formula; see text) for an oral dose where kaR is the apparent first-order absorption rate constant and beta R is the rate constant that describes the decline in blood concentrations of drug at 24-h intervals, i.e., 12, 36, and 60 or 24, 48, and 72 h, etc. AUC0-24 can be calculated by trapezoidal summation. The precision of this method is dependent on the number of observations during the 0-24 h sampling period as well as the accuracy of kaR and beta R. For drugs that are subject to a distinct distribution phase(s), error can be introduced into the AUC0-infinity value if pseudo-equilibrium has not been achieved during the first 24-hour interval. Although the method depends on a linearization process, it is truly concompartmental ('model-independent') in nature.