Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin
| العنوان: | Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin |
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| المؤلفون: | Roberta Natália Cestari, Glauco Henrique Balthazar Nardotto, Leandro Francisco Pippa, Adriana Rocha, Eduardo Antônio Donadi, Vera Lucia Lanchote, Renê Donizeti Ribeiro de Oliveira, F.F. Souza |
| المصدر: | Clinical and Translational Science Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 030213 general clinical medicine, Metabolite, Atorvastatin, Pharmacology, Severity of Illness Index, 030226 pharmacology & pharmacy, chemistry.chemical_compound, 0302 clinical medicine, ESTATINAS, Cytochrome P-450 CYP3A, Lupus Erythematosus, Systemic, General Pharmacology, Toxicology and Pharmaceutics, skin and connective tissue diseases, Chemokine CCL2, Volume of distribution, Liver-Specific Organic Anion Transporter 1, General Neuroscience, Area under the curve, Articles, General Medicine, Middle Aged, Healthy Volunteers, Interleukin-10, Area Under Curve, Female, Signal Transduction, medicine.drug, Adult, Adolescent, Metabolic Clearance Rate, Midazolam, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Pharmacokinetics, medicine, Humans, Autoimmune disease, CYP3A4, Tumor Necrosis Factor-alpha, business.industry, Research, medicine.disease, chemistry, Case-Control Studies, business |
| الوصف: | The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0–4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP‐1 and TNF‐α, while the uncontrolled SLE group also showed higher plasma concentrations of IL‐10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76–83.56) vs. 30.56 (22.69–41.15) ng⋅hour/mL) and its inactive metabolite ATV‐lactone (98.74 (74.31–131.20) vs. 49.21 (34.89–69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30–457.00) vs. 654.5 (486.00–881.4) L/hour) and apparent volume of distribution (2,609 (1,607–4,234) vs. 7,159 (4,904–10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV‐lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE. |
| تدمد: | 1752-8062 1752-8054 |
| DOI: | 10.1111/cts.12808 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d764e7d10827aa8b77baec095177e83 https://doi.org/10.1111/cts.12808 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0d764e7d10827aa8b77baec095177e83 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17528062 17528054 |
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| DOI: | 10.1111/cts.12808 |