Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey.
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.
Shou
Magang
M
Department of Drug Metabolism, Merck Research Laboratories, WP75A-203, West Point, PA 19486, USA. magang_shou@merck.com
Lu
Wei
W
Kari
Prasad H
PH
Xiang
Cathie
C
Liang
Yuexia
Y
Lu
Ping
P
Cui
Dan
D
Emary
W Bart
WB
Michel
Kimberly B
KB
Adelsberger
Jennifer K
JK
Brunner
Janice E
JE
Rodrigues
A David
AD
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
D015262:Xenobiotics