|A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats|
|Li, Liang2; Li, Zai-quan3; Deng, Chen-hui2; Ning, Miao-ran2; Li, Han-qing2; Bi, Shan-shan2; Zhou, Tian-yan1,2; Lu, Wei1,2|
|关键词||Drug-drug Interactions Dexamethasone Cyp Induction Cyp3a1/2 Pharmacokinetics Pharmacodynamics Nonmem|
|刊名||ACTA PHARMACOLOGICA SINICA|
|WOS标题词||Science & Technology|
|类目[WOS]||Chemistry, Multidisciplinary ; Pharmacology & Pharmacy|
|研究领域[WOS]||Chemistry ; Pharmacology & Pharmacy|
|关键词[WOS]||VS. SEQUENTIAL-ANALYSIS ; PREGNANE X RECEPTOR ; IN-VITRO ; LIVER-MICROSOMES ; FEMALE RATS ; PHARMACOKINETICS ; METABOLISM ; EXPRESSION ; TOXICITY ; HEPATOCYTES|
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 post-treatment. 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.
|作者单位||1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China|
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Radiat Med, Beijing 100191, Peoples R China
|Li, Liang,Li, Zai-quan,Deng, Chen-hui,et al. A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats[J]. ACTA PHARMACOLOGICA SINICA,2012,33(1):127-136.|
|APA||Li, Liang.,Li, Zai-quan.,Deng, Chen-hui.,Ning, Miao-ran.,Li, Han-qing.,...&Lu, Wei.(2012).A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats.ACTA PHARMACOLOGICA SINICA,33(1),127-136.|
|MLA||Li, Liang,et al."A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats".ACTA PHARMACOLOGICA SINICA 33.1(2012):127-136.|