MK-571 sodium salt hydrate, as a potent and specific antagonist of leukotriene D4 action, used for treatment of asthma[1].
In vitro test it shown that with 0.01-100 μM MK-571 reduced the export of 3H-S1P from erythrocytes in a concentration-dependent manner[2]. In vitro efficacy test it exhibited that 12.5-50 μM MK-571 in both aortic and brain derived ECs has more obvious supress-the efflux of agents rate than that of verapamil[3]. MK-571 has inhibition against LTC4 transport with IC50 of 1.0 μM[4].
In vivo, treatment with 8-32 mg/kg MK-571 intravenously in mice caused dose-dependent protection against acetic-acid-induced abdominal constriction with ED50 of 30 mg/kg[5]. In vivo, mice were instilled after endotoxin instillation at doses of 15, 35, or 50 mg/kg, MK-571 obviously inhibited the influx of inflammatory cells and reduced pro-inflammatory cytokines in BALF in a dose-dependent manner[6]. In addition, 10 ug/eye completely inhibited in vivo chemotactic responses to LTD4, and partially inhibited (54%) the responses to ovalbumin[7]. In vivo, pretreatment with 1 mg/kg MK-571 orally markedly inhibited the OA(ovalbumin)-induced EO (eosinophils) migration[8] . Treatment with 1 mg/kg/day MK-571 for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, MK-571 had effective inhibition of myointimal VSMC (vascular smooth muscle cell) proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening[9].
References:
[1] Tocco DJ, et al. Interspecies differences in stereoselective protein binding and clearance of MK-571. Drug Metab Dispos. 1990 Jul-Aug;18(4):388-92.
[2] Christensen PM, et al. Apolipoprotein M mediates sphingosine-1-phosphate efflux from erythrocytes. Sci Rep. 2017 Nov 8;7(1):14983.
[3] Eilers M, et al. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood). 2008 Sep;233(9):1149-60.
[4] Schaub T, et al. ATP-dependent leukotriene export from mastocytoma cells. FEBS Lett. 1991 Feb 11;279(1):83-6.
[5] G?k S, et al. The antinociceptive effect of leukotriene D(4) receptor antagonist, MK-571, in mice: possible involvement of opioidergic mechanism. Eur J Pharmacol. 1999 Dec 15;386(2-3):195-200.
[6] Hao Q, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Decrease Lung Injury in Mice. J Immunol. 2019 Oct 1;203(7):1961-1972.
[7] Chan CC, et al. Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. Eur J Pharmacol. 1990 Dec 4;191(3):273-80.
[8] Foster A, et al. Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Int Arch Allergy Appl Immunol. 1991;96(3):279-84.
[9] Porreca E, et al. Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Thromb Haemost. 1996 Jul;76(1):99-104.
MK-571 钠盐水合物,作为白三烯 D4 作用的强效特异性拮抗剂,用于治疗哮喘[1]。
体外试验表明,0.01-100 μM MK-571 以浓度依赖性方式减少红细胞中 3H-S1P 的输出[2]。体外药效试验表明,12.5-50 μM MK-571在主动脉和脑源性ECs中均比维拉帕米[3]具有更明显的抑制药物流出率的作用。 MK-571 抑制 LTC4 转运,IC50 为 1.0 μM[4]。
在体内,小鼠静脉注射 8-32 mg/kg MK-571 后,ED50 为 30 mg/kg[5],对醋酸诱导的腹部收缩产生剂量依赖性保护作用.在体内,小鼠以15、35或50 mg/kg的剂量滴注内毒素后,MK-571以剂量依赖的方式明显抑制BALF中炎症细胞的流入和促炎细胞因子的减少[ 6]。此外,10 ug/eye 完全抑制体内对 LTD4 的趋化反应,并部分抑制 (54%) 对卵清蛋白的反应[7]。在体内,口服 1 mg/kg MK-571 预处理可显着抑制 OA（卵清蛋白）诱导的 EO（嗜酸性粒细胞）迁移[8]。在大鼠颈动脉球囊导管损伤模型中,用 1 mg/kg/day MK-571 治疗至少 1 天后,MK-571 可有效抑制肌内膜 VSMC（血管平滑肌细胞）增殖,具有 58新内膜中 5-溴-2'-脱氧尿苷 (BrdU) 摄取减少 %,新内膜增厚减少 69%[9]。