Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.
Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.
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DOI：
10.1111/cts.12808
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Lanchote VL
中科院分区：
文献类型：
--
作者：
Cestari RN;de Oliveira RDR;de Souza FFL;Pippa LF;Nardotto GHB;Rocha A;Donadi EA;Lanchote VL
本研究以阿托伐他汀（ATV）为探针药物，评估了系统性红斑狼疮（SLE）活动（一种慢性炎症性自身免疫性疾病）对窦状隙摄取转运蛋白OATP 1B 1的影响。15例健康受试者，13例控制SLE患者（SLEDAI 0-4），12例未控制SLE患者（SLEDAI 6 - 15），均为女性。咪达唑仑（MDZ）的表观总清除率（CYP 3A 4活性的标志物）在三个研究组之间没有变化。控制和未控制的SLE组显示出较高的MCP-1和TNF-α血浆浓度，而未控制的SLE组也显示出较高的IL-10血浆浓度。未控制SLE组显示ATV曲线下面积（AUC）较高（60.47（43.76-83.56）对比30.56（22.69-41.15）ng·h/mL）及其非活性代谢物ATV-内酯（98.74（74.31-131.20）对比49.21（34.89-69.42）ng·h/mL），表观总清除率较低（330.7（239.30-457.00）对比654.5（486.00-881.4）L/h）和表观分布容积（2，609（1，607 - 4，234）vs. 7，159（4，904 - 10，450）L），与健康受试者组相比（几何平均值和95%置信区间）。ATV及其代谢产物的药代动力学在健康受试者组和SLE控制组之间没有差异。总之，一旦通过MDZ的口服清除率评估的体内CYP 3A 4活性未改变，不受控制的SLE增加了ATV和ATV-内酯的全身暴露量，推断OATP 1B 1活性受到抑制。炎症状态，而不是疾病本身，是不受控制的SLE组中描述的OATP 1B 1抑制的结果，因为在控制的SLE患者中，ATV及其代谢产物的全身暴露没有改变。
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.
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影响因子：
6.7
作者：
Machavaram, K. K.;Almond, L. M.;Kenny, J. R.
通讯作者：
Kenny, J. R.
DOI：
10.1016/s0197-2456(98)00037-3
发表时间：
1998-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Dupont, WD;Plummer, WD
通讯作者：
Plummer, WD
影响因子：
2.6
作者：
Demir, S.;Artim-Esen, B.;Inanc, M.
通讯作者：
Inanc, M.
影响因子：
3.2
作者：
Liu, Yan-Mei;Pu, Hua-Hua;Yu, Chen
通讯作者：
Yu, Chen
DOI：
10.1016/j.berh.2005.03.010
发表时间：
2005-10-01
影响因子：
5.2
作者：
Griffiths, B;Mosca, M;Gordon, C
通讯作者：
Gordon, C