RT Journal Article
SR Electronic
T1 A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 80
OP 87
VO 18
IS 1
A1 R L Semmes
A1 D D Shen
YR 1990
UL http://dmd.aspetjournals.org/content/18/1/80.abstract
AB 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.