A physiologically realistic model was used to investigate through simulation the multiple-dose behavior of drugs subject to enterohepatic cycling. The model included separate liver and gallbladder compartments and instantaneous emptying of the gallbladder at regular intervals of length phi. Two half-lives are described, only one of which is predictive of time to steady state and accumulation. This predictive half-life would be obtained if plasma samples were taken at regular intervals equal to phi, and has been termed the effective half-life. Incorporation of gallbladder emptying at irregular intervals into the model did not materially alter our conclusions regarding the existence and predictive nature of the effective half-life.