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Evaluation of systemic lupus erythematosus effect on OATP1B1 carrier activity applying atorvastatin PK-PD modeling

Grant number: 15/02754-8
Support type:Regular Research Grants
Duration: February 01, 2016 - September 30, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Vera Lúcia Lanchote
Grantee:Vera Lúcia Lanchote
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Adriana Rocha ; Eduardo Antônio Donadi ; Eduardo Barbosa Coelho ; Maria Paula Marques Pereira


Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with prevalence of 20-150 cases per 100,000 inhabitants/population. Cardiovascular diseases are major causes of morbidity and mortality in patients with SLE, for which statins have shown to be the most effective strategy in the treatment of dyslipidemia and prevention of atherosclerosis. Classically, statins are endocytosed by hepatocytes through the OATP1B1 transporter, where they inhibit HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid during the synthesis of cholesterol. However, studies have shown that inflammatory diseases such as SLE are associated with changes in the activity of drug transporters, such as OATP1B1 and MDR1, as well as the CYP enzymes involved in metabolism. Considering that statins are substrates of OATP1B1, MDR1 transporters and are metabolized by CYP3A4, our hypothesis is that patients with SLE could differ from the general population in terms of pharmacokinetics and pharmacodynamics of atorvastatin due to the decrease in OATP1B1 activity, with a consequent reduction the influx of the statin in the hepatocyte and thus its pharmacodynamics effect. To test our hypothesis, we propose to evaluate the in vivo activity of hepatic OATP1B1 using PK-PD modeling of atorvastatin, using the plasma concentration of atorvastatin as a pharmacokinetic parameter and plasma concentration of mevalonic acid and non-esterified fatty acids as pharmacodynamics parameters. (AU)