A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair.

An analytic expression for the plasma clearance of a drug, which undergoes enterohepatic circulation (EHC) in intact form and in the form of a hydrolyzable conjugate metabolite, was derived based on a four-compartment model that features the three successive steps of the recycling cascade: biliary excretion, intestinal hydrolysis, and reabsorption. The kinetic equation consists of irreversible and partially reversible clearance terms. The irreversible terms represent the removal of drug from the systemic circulation in a unidirectional fashion, such as renal clearance and extraconjugative biotransformation pathways. The reversible terms represent the two recycle pathways: biliary excretion of the parent compound, and the formation of a conjugate metabolite and its subsequent excretion into bile. Mathematically, the reversible clearance terms can be resolved into the product of a net recycled fraction and an irreversible clearance estimate for either biliary excretion or conjugate formation. The net recycled fractions are, in turn, a function of the competitive kinetics of drug or drug conjugate at each step of the EHC cascade. The derived clearance equation provides a useful conceptual framework in the kinetic analysis of factors controlling the reversibility of plasma drug clearance as a result of EHC. Analysis of the model also points to the development of new experimental strategies in elucidating the EHC of xenobiotics.