CPSA Shanghai 2011
Changing Paradigm in Drug Discovery & Development:
East Meets West
April 13 - 16, 2011
Renaissance Shanghai Pudong Hotel
Shanghai, China
Abstract
Friday PM - Parallel Session III
Mechanism-based Pharmacokinetic/Pharmacodynamic Model for CYP3A Induction by Dexamethasone in Rat
Liang Li, TianYan Zhou and Wei Lu*
a: State Key Laboratory of Nature and Biomimetic Drugs (Peking University)
Beijing 100191, China
b: Department of Pharmaceutics, School of Pharmaceutical Sciences
Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China
The aim of this study was to develop a pharmacokinetic/pharmacodynamic link model to describe mechanistic receptor/gene-mediated CYP3A1/2 induction by dexamethasone (DEX) in male Sprague-Dawley rats. Animals were randomized to receive either DEX (100 mg·kg−1 in 5 ml·kg−1 of corn oil) or corn oil alone (solvent) by intraperitoneal injection and sacrificed at various time points up to 60h post-treatment. Blood and livers were collected to measure DEX plasma concentration, CYP3A1/2 mRNA and CYP3A1/2 enzyme activity. Software NONMEM (Version VII) was used for data analysis and model development. A two-compartment model with Michaelis-Menten absorption from the injection site was applied to describe pharmacokinetic behavior of DEX. Vmax, Km and system clearance were 9770 µg/hr, 2.98 µg/mL, and 157 mL/hr, respectively. A sigmoid model with dissociation constant (Kd) and Hill coefficient (γ) was developed for the dynamics of CYP3A1/2 mRNA induction by activated DEX/PXR complex. Maximum induction levels of CYP3A1 and CYP3A2 mRNA reached 17.97- and 5.59-fold at 24 and 42 hours after administration, then returned to baseline by 24 and 12 hours, respectively. An indirect response model was used to account for the delayed up-regulation of CYP3A1/2 enzyme activity after CYP3A1/2 mRNA induction. CYP3A1/2 enzyme activity increased up to 2.93-fold with a lag time of 32 hours after DEX reached its peak plasma concentration.
*Corresponding author. Tel: +86-10-82801717; Fax: +86-10-82801717 E-mail: luwei_pk@bjmu.edu.cn