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期刊论文

Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey

卢炜Magang Shou a* Wei Lu b Prasad H. Kari a Cathie Xiang a Yuexia Liang a Ping Lua Dan Cui a W. Bart Emary a Kimberly B. Michel a Jennifer K. Adelsberger a Janice E. Brunner a A. David Rodrigues a

European Journal of Pharmaceutical Sciences 26(2005)151-161,-0001,():

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摘要/描述

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 (T1/2) 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 0.33Lh−1, IV; from 2.3 to 0.4Lh−1, PO), and an increase in T1/2 (from 0.9 to 18 h, IV) and in AUC (from 1.5 to 17.4gh/mL, IV; from 2.8 to 16.3gh/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.

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