Research Article Details
| Article ID: | A17856 |
| PMID: | 27522101 |
| Source: | Drug Metab Pers Ther |
| Title: | Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease. |
| Abstract: | BACKGROUND: Severe forms of non-alcoholic fatty liver disease (NAFLD) adversely affect the liver physiology and hence the pharmacokinetics of drugs. Here, we investigated the effect of NAFLD on the pharmacokinetics of rosiglitazone, an insulin sensitizer used in the treatment of type 2 diabetes. METHODS: Male C57BL/6 mice were divided into two groups. The first group (n=14) was fed with normal chow feed and the second group (n=14) was fed with 60% high-fat diet (HFD) and 40% high fructose liquid (HFL) for 60 days to induce NAFLD. The development of NAFLD was confirmed by histopathology, liver triglyceride levels and biochemical estimations, and used for pharmacokinetic investigations. Rosiglitazone was administered orally at 30 mg/kg dose. At predetermined time points, blood was collected and rosiglitazone concentrations were determined using LC/MS/MS. Plasma concentrations were subjected to non-compartmental analysis using Phoenix WinNonlin (6.3), and the area under the plasma concentration-time curve (AUC) was calculated by the linear-up log-down method. RESULTS: HFD and HFL diet successfully induced NAFLD in mice. Rosiglitazone pharmacokinetics in NAFLD animals were altered significantly as compared to healthy mice. Rosiglitazone exposure increased significantly in NAFLD mice (2.5-fold higher AUC than healthy mice). The rosiglitazone oral clearance was significantly lower and the mean plasma half-life was significantly longer in NAFLD mice as compared to healthy mice. CONCLUSIONS: The NAFLD mouse model showed profound effects on rosiglitazone pharmacokinetics. The magnitude of change in rosiglitazone pharmacokinetics is similar to that observed in humans with moderate to severe liver disease. The present animal model can be utilized to study the NAFLD-induced changes in the pharmacokinetics of different drugs. |
| DOI: | 10.1515/dmpt-2016-0008 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D366 | Thiazolidinediones | Chemical drug | DB11898 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D311 | Rosiglitazone | Chemical drug | DB00412 | PPARG agonist; PPARA; PPARD | Improve insulin resistance | Failed in clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |