Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.
Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.
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ProbEnecid是一种有机阴离子转运蛋白1和3抑制剂，增加了N-乙酰半胱氨酸的血浆和大脑暴露。
DOI：
10.1080/00498254.2016.1187777
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Empey PE
中科院分区：
文献类型：
--
作者：
Hagos FT;Daood MJ;Ocque JA;Nolin TD;Bayir H;Poloyac SM;Kochanek PM;Clark RS;Empey PE
n -乙酰半胱氨酸（NAC）作为一种抗氧化剂被研究用于多种疾病，包括创伤性脑损伤，但其穿越膜屏障的机制尚不清楚。我们试图了解转运蛋白抑制剂probenecid如何影响NAC的药代动力学，并评估NAC与转运蛋白的相互作用。幼年Sprague-Dawley大鼠单独或与probenecid联合腹腔注射NAC。依次采集血浆和脑组织标本，测定NAC浓度。转运体研究采用过表达有机阴离子转运蛋白（OAT）1或OAT3和人多药耐药相关蛋白（MRP）1或MRP4膜囊的人胚胎肾-293细胞进行。血浆NAC曲线下面积增加1.65倍，脑组织NAC曲线下面积增加2.41倍。表观血浆清除率降低65%。用OAT1和OAT3观察了丙酮酸对NAC摄取的时间和浓度依赖性。MRP1或MRP4未观察到NAC摄取。我们的研究结果首次表明NAC是OAT1和OAT3的底物，而probenecid增加了体内NAC的血浆和脑暴露。这些数据提供了关于NAC如何跨越生物屏障的见解，并提出了增加NAC暴露的有希望的治疗策略。
N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We sought to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.
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影响因子：
--
作者：
PRESCOTT, LF;ILLINGWORTH, RN;PROUDFOOT, AT
通讯作者：
PROUDFOOT, AT
DOI：
10.1152/ajprenal.00272.2005
发表时间：
2006-04-01
影响因子：
4.2
作者：
Erdman, AR;Mangravite, LM;Giacomini, KM
通讯作者：
Giacomini, KM
影响因子：
5.8
作者：
Giustarini, Daniela;Milzani, Aldo;Rossi, Ranieri
通讯作者：
Rossi, Ranieri
影响因子：
3.6
作者：
Koh, AS;Simmons-Willis, TA;Ballatori, N
通讯作者：
Ballatori, N
影响因子：
4.9
作者：
LASKIN, OL;DEMIRANDA, P;LIETMAN, PS
通讯作者：
LIETMAN, PS