A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Abstract

Aim: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. Methods: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h posttreatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NON-MEM version 7.1.2. Results: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg --1 ·h -1 , 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29-and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. Conclusion: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug-and system-specific PK/PD parameters for the course of induction.

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism

“…In rat, CYP3A2 is the main constitutive liver enzyme; sharing 73% homology in the amino acid sequence, some substrate preference and functional analogies to human CYP3A4 [71], which metabolizes a wide range of drugs and endogenous compounds. Our finding that MPL enhances CYP3A2 expression in the rat is in line with previous findings that dexamethasone (DEX) induces CYP3A2 mRNA and protein expression as well as enzyme activity in rat liver [72]. …”

Effect of panaxytriol on cytochrome P450 3A4 via the pregnane X receptor regulatory pathway

“…However, a previous study showed that PXT inhibited the expression of CYP3A1/2 mRNA in rat primary hepatocytes. CYP3A1/2 was predominant in rat liver, whereas CYP3A4 was predominant in human hepatocytes and HepG2 cells (Li et al, ). The species difference in CYP3A enzymes and their nuclear receptors between humans and rats may be a crucial factor explaining this differential regulation effect.…”

In vitro and in vivo characterization of CYP inhibition by 1‐aminobenzotriazole in rats

“…The AUC ratio (MDZ) is the increase in MDZ exposure due to ABT when compared with the MDZ exposure without ABT pretreatment. The rate constant for enzyme degradation in the liver, k deg,h , was fixed to the literature value of 6.9 × 10 −4 min −1 . The average concentration of ABT over 24 h from each study was used as [ I ] h .…”

“…The rate constant for enzyme degradation in the liver, k deg,h , was fixed to the literature value of 6.9 × 10 À4 min À1 [15]. The average concentration of ABT over 24 h from each study was used as [I] h .…”