| 名稱 | Ivacaftor |
| 描述 | Ivacaftor (VX-770) (VX-770) is a potentiator of CFTR targeting G551D-CFTR (EC50: 100 nM) and F508del-CFTR (EC50: 25 nM) in Fisher rat thyroid cells, respectively. |
| 細(xì)胞實(shí)驗(yàn) | HEK293 cells were seeded on poly-lysine precoated six-well plates at a density of 1.3 x 10^6 cells/well. Six hours after seeding, cells were transiently transfected with 1μg of ABCB4-encoding plasmids using Turbofect, following the manufacturer's instructions. Twenty-four hours post-transfection, cells were washed twice with HBSS, then the medium was replaced by phenol red-free DMEM containing 0.5 mmol/L sodium taurocholate and 0.02% fatty acid–free bovine serum albumin (BSA) in the presence or absence of 10 μmol/L of ivacaftor, 50 μM/L of UDCA, and 10 μmol/L of ivacaftor plus 50 μM/L of UDCA. Media were collected after 24 hours [2]. |
| 動(dòng)物實(shí)驗(yàn) | Male mouse,Sprague?Dawley rats,beagle dog,and cynomolgus monkeys (n = 3/group) were administered a single iv dose of compound formulated in dimethyl isosorbide/ethanol/PEG400/5% dextrose in water (D5W) (10%/15%/35%/40%) at the nominal dose indicated in a dose volume of 1 mL/kg.Blood samples (0.3 mL,sodium heparin anticoagulant) were collected from an indwelling carotid cannula at the following nominal time points: at predose,5,15,30,and 45 min and 1,2,4,6,8,12,24,36,and 48 h following iv administration and at predose,0.25,0.50,1,1.5,2,4,8,12,and 24 h following oral administration.The concentration of compound in the plasma samples was determined with a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method,which had a lowest limit of quantitation (LLOQ) of 1 ng/mL and a linearity range between 1 and 2500 ng/mL [3]. |
| 體外活性 | VX-770將溫度修正的F508del-FRT細(xì)胞中，通過forskolin刺激的IT增加約6倍，其EC50為25 ± 5 nM。在加入VX-770之前，CFTR通道已經(jīng)暴露于PKA（75 nM）和ATP（1 mM）的最大有效濃度下。在這些條件下，10 μM VX-770將G551D CFTR的Po增加了約6倍[1]。暫時(shí)表達(dá)ABCB4-wt或突變體的HEK293細(xì)胞，被10 μmol/L的ivacaftor（VX-770）處理24小時(shí)。ivacaftor處理使ABCB4-G535D的PC分泌活性增加3倍，ABCB4-G536R增加13.7倍，ABCB4-S1076C增加6.7倍，ABCB4-S1176L增加9.4倍，以及ABCB4-G1178S增加5.7倍[2]。 |
| 體內(nèi)活性 | 在大鼠劑量比例性研究中，通過口服懸浮劑型給藥，Ivacaftor的劑量從1到200 mg/kg（中間劑量為3, 10, 30和100）時(shí)，其AUC和Cmax呈線性增加。在比格犬中，口服劑量從3到80 mg/kg（中間劑量為10, 30和60）增加時(shí)，觀察到類似趨勢(shì)，證實(shí)了高水平的口服吸收。通過從四種物種的異速生長(zhǎng)估計(jì)，預(yù)測(cè)人類對(duì)Ivacaftor的肝臟清除率為4.7 mL min1 kg1，約占肝血流量的23% [3]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 55 mg/mL (140.13 mM)
|
| 關(guān)鍵字 | Cystic fibrosis transmembrane conductance regulator | Ivacaftor | inhibit | CFTR | VX 770 | Autophagy | Inhibitor | VX770 |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Valproic Acid | Taurine | Gefitinib | Aceglutamide | Hydroxychloroquine | Curcumin | Stavudine | Salicylic acid | Paeonol | Sodium 4-phenylbutyrate |
| 相關(guān)庫(kù) | 經(jīng)典已知活性庫(kù) | 已知活性化合物庫(kù) | EMA 上市藥物庫(kù) | FDA 上市藥物庫(kù) | 離子通道庫(kù) | 藥物功能重定位化合物庫(kù) | 抗癌臨床化合物庫(kù) |