A Time-Lag Model for Pharmacokinetics of Drugs Subject to Enterohepatic Circulation

A two-compartment model with time lag is proposed to describe the pharmacokinetics of drugs subject to enterohepatic circulation. The basic model, including two compartments for body and GI tract, respectively, with elimination occurring from both compartments, was previously proposed. The assumption that the reabsorption of a drug molecule is delayed after its biliary excretion is expressed by the addition of a time lag in the transfer from the first to the second compartment. Computer simulation of the model for intravenous bolus injection and oral intake of the drug was performed through first-order numerical integration. Several qualitative results concerning changes in pharmacokinetics due to modifications in biliary excretion, in reabsorption, or in elimination are identical with predictions using the basic model. However, several qualitative and quantitative results were significantly different. The pharmacokinetics, though remaining linear, are no longer biexpo-nential. Initial decay after intravenous injection was not affected by modifications in reabsorption or elimination from intestine. Predictions based on the time-delay model agree with existing experimental evidence concerning pharmacokinetics of substances undergoing enterohepatic cycling. Delayed recirculation may lead to rebounds in plasma level profiles as well as after intravenous and oral administration. The half-life of the drug is significantly prolonged even when the kinetic processes involved in recirculation remain unchanged.