title: Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey.
abstract: Enterohepatic recirculation (EHR) occurs via biliary excretion and intestinal reabsorption of a drug. Drug recycling through EHR can lead to a change in pharmacokinetic (PK) properties, such as reduced clearance (CL), extended half-life (T(1/2)) and increased plasma exposure (AUC). As a result, EHR may prolong the pharmacological effect of drugs. In the present study, the compound (Cpd A) was found to exhibit EHR in Rhesus monkeys associated with a reduction in CL (from 3.8 to 0.33 Lh(-1), IV; from 2.3 to 0.4 Lh(-1), PO), and an increase in T(1/2) (from 0.9 to 18 h, IV) and in AUC (from 1.5 to 17.4 microg h/mL, IV; from 2.8 to 16.3 microg h/mL, PO), by comparing the PK in the monkeys via the interruption of EHR (bile-duct cannulation) with that in the intact monkeys. A population four-compartment model was constructed based on recirculation loops incorporating all possible inputs (bile secretion, a lag-time model for gall bladder emptying, routes and amounts of a single dose administration) to fully evaluate the EHR of Cpd A. The plasma concentrations versus time profiles predicted from the model had a good fit to the values observed in the subjects and were further simulated with 90% confidence interval to demonstrate its utility. Thus, the model could be applied as a useful tool to evaluate the drugs or compounds that undergo EHR in different species.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, WP75A-203, West Point, PA 19486, USA. magang_shou@merck.com
authors.forename: Magang
authors.initials: M
authors.lastname: Shou
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Prasad H
authors.initials: PH
authors.lastname: Kari
authors.forename: Cathie
authors.initials: C
authors.lastname: Xiang
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Liang
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Dan
authors.initials: D
authors.lastname: Cui
authors.forename: W Bart
authors.initials: WB
authors.lastname: Emary
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Michel
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Adelsberger
authors.forename: Janice E
authors.initials: JE
authors.lastname: Brunner
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D003135:Common Bile Duct / Q000601:surgery; D004764:Enterohepatic Circulation; D006207:Half-Life; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010599:Pharmacokinetics; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D015262:Xenobiotics