title: Mechanism-based pharmacokinetic-pharmacodynamic modeling of salvianolic acid A effects on plasma xanthine oxidase activity and uric acid levels in acute myocardial infarction rats.
abstract: 1. Salvianolic acid A (SalA) was found to attenuate plasma uric acid (UA) concentration and xanthine oxidase (XO) activity in acute myocardial infraction (AMI) rats, which was characterized with developed mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model. 2. AMI was induced in rats by coronary artery ligation. Surviving AMI rats received a single intravenous dose of 5 mg/kg of SalA and normal saline. The plasma SalA concentrations were determined by HPLC-MS/MS method. The plasma UA concentrations were determined by HPLC method and plasma XO activity were measured spectrophotometrically. An integrated mathematical model characterized the relationship between plasma UA and SalA. 3. Pharmacokinetics was described using two-compartment model for SalA with linear metabolic process. In post-AMI rats, XO activity and UA concentrations were increased, while SalA dosing palliated this increase. These effects were well captured by using two series of transduction models, simulating the delay of inhibition on XO driven by SalA and UA elevation resulted from the multiple factors, respectively. 4. The effect was well described by the developed PK-PD model, indicating that SalA can exert cardiovascular protective effects by decreasing elevated plasma UA levels induced by AMI.
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Liu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: He
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D007773:Lactates / Q000378:metabolism* / Q000493:pharmacokinetics; D008954:Models, Biological; D009203:Myocardial Infarction / Q000378:metabolism*; D010599:Pharmacokinetics; D010949:Plasma; D051381:Rats; D014527:Uric Acid / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000097:blood*
chemical_list: D002109:Caffeic Acids; D007773:Lactates; D014527:Uric Acid; C066201:salvianolic acid A; D014969:Xanthine Oxidase
keywords: Acute myocardial infarction; PK-PD modeling; salvianolic acid A; uric acid; xanthine oxidase