Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin

Autor: 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
Rok vydání: 2020
Předmět:
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
Zdroj: Clinical and Translational Science
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.12808
Popis: 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.
Databáze: OpenAIRE
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