ABSTRACT
CONTEXT: Succinic acid and irbesartan are commonly used drugs in cardiovascular disease treatment. The interaction might occur during their co-administration, which was still unclear. OBJECTIVE: To reveal the effect of succinic acid on the metabolism of irbesartan and its potential mechanism. MATERIALS AND METHODS: The Sprague-Dawley rats (n = 6) were treated with a single dose of 30 mg/kg irbesartan (control) or the co-administration with the pre-treatment of 200 mg/kg succinic acid for 7 d. The effect of succinic acid on the metabolic stability and the activity of CYP2C9 was evaluated in rat liver microsomes. RESULTS: Succinic acid increased the AUC (5328.71 ± 959.31 µg/L × h vs. 3340.23 ± 737.75 µg/L × h) and prolonged the half-life of irbesartan (from 12.79 ± 0.73 h to 20.59 ± 6.35 h). The Tmax (2.83 ± 0.75 h vs. 3.83 ± 1.10 h) and clearance rate (3.46 ± 1.13 L/h/kg vs. 6.91 ± 1.65 L/h/kg) of irbesartan was reduced by succinic acid. Consistently, succinic acid improved the metabolic stability (half-life from 23.32 ± 3.46 to 27.35 ± 2.15 min, intrinsic clearance rate from 59.43 ± 6.12 to 50.68 ± 5.64 µL/min/mg protein). Succinic acid was also found to inhibit the activity of CYP2C9 with the IC50 value of 13.87 µM. DISCUSSION AND CONCLUSIONS: Succinic acid increased the system exposure of irbesartan via inhibiting CYP2C9. The experiment design of this study also provides a reference for the further validation of this interaction in humans.
Subject(s)
Cytochrome P-450 CYP2C9 Inhibitors/pharmacology , Irbesartan/pharmacokinetics , Microsomes, Liver/metabolism , Succinic Acid/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Animals , Area Under Curve , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Half-Life , Inhibitory Concentration 50 , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND The aim of this study was to assess the effect of combined use of Astragaloside IV(AsIV) and atorvastatin (AV) on the expression of PPAR-γ and inflammation-associated cytokines in atherosclerosis rats. MATERIAL AND METHODS High-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma were detected through automatic biochemical analyzer and the histopathological analysis was performed via HE staining. The levels of oxidized low-density lipoprotein (oxLDL) and tumor necrosis factor-α (TNF-α), and interleukins (IL)-6 and IL-18 in serum were detected by ELISA. The expressions of proliferator-activated receptor-gamma (PPAR-γ), cluster of differentiation 36 (CD36), matrix metalloprotein-9 (MMP-9), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), and p38 and P-p38 levels were detected by Western blot. RT-PCR was used to detect the mRNA expressions of nuclear factor-κB (NF-κB), PPAR-γ, CD36, MMP-9, ICAM-1, and VCAM-1. RESULTS Administration of AsIV and AV significantly decreased the lipid content and oxLDL in plasma. The levels of TNF-α, IL-6, and IL-18 were significantly decreased in AsIV, AV, and AsIV + AV groups, especially in the AsIV + AV group. Administration decreased the levels of NF-κB, CD36, MMP-9, ICAM-1, VCAM-1, and P-p38 expression and increased the expression of peroxisome PPAR-γ. Compared with the NC group, the atherosclerotic lesions significantly increased in the HD group, while the combined administration significantly inhibited the development of atherosclerotic disease. CONCLUSIONS Combined administration of AV and AsIV showed potent effects against atherosclerosis through the NF-κB/PPARγ pathway, which may be a new therapy for treatment of atherosclerosis in the future.
Subject(s)
Atherosclerosis/drug therapy , Atorvastatin/pharmacology , PPAR gamma/drug effects , Saponins/pharmacology , Triterpenes/pharmacology , Animals , China , Cytokines/drug effects , Disease Models, Animal , Drug Therapy, Combination/methods , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-6/metabolism , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Male , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Many studies investigated the association between intercellular adhesion molecule 1 (ICAM-1) gene rs5498 polymorphism and the risk of coronary artery disease (CAD). However, the results were inconsistent. METHODS: To clarify convincing association, we conducted a comprehensive meta-analysis by searching in PubMed, Embase, Web of sciences, Sciences citation index, Google scholar, Cochrane Library, and the CNKI databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 29 case-control studies with 5,494 cases and 6,364 controls for rs5498 polymorphism were included. The studied populations of this meta-analysis included Caucasians and Asians. Meta-analysis showed that rs5498 polymorphism was associated with the decreased risk of CAD. Stratification analysis of ethnicity found that rs5498 polymorphism decreased the risk of CAD among Caucasians, but not among Asians. Stratification by type of CAD revealed that ICAM-1 gene rs5498 polymorphism was also correlated with the decreased risk of myocardial infarction (MI). CONCLUSION: In conclusion, this meta-analysis indicates that ICAM-1 gene rs5498 polymorphism decreases the risk of CAD.