title: A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: R L
authors.initials: RL
authors.lastname: Semmes
authors.forename: D D
authors.initials: DD
authors.lastname: Shen
mesh_terms: D001646:Bile / Q000378:metabolism; D004764:Enterohepatic Circulation; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations