Intestinal OCTN2-and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.

孕酮对OCTN2的抑制作用及对左旋肉碱肾脏排泄的影响

目的考察孕酮对肉碱/有机阳离子转运体2(carnitine/organic cation transporter 2,OCTN2)功能的影响,并探讨其是否通过抑制肾脏OCTN2功能改变左旋肉碱肾脏排泄,从而降低妊娠期血浆左旋肉碱浓度。方法采用已构建的稳定高表达人OCTN2的MDCK-hOCTN2细胞模型,分别以米屈肼和氘代左旋肉碱为底物,考察孕酮对OCTN2的抑制作用。正常雌性ICR小鼠皮下注射孕酮,使其达妊娠晚期血清孕酮浓度,比较其与对照组小鼠左旋肉碱尿液排泄差异,以及血浆和各组织中左旋肉碱浓度差异。结果孕酮显著抑制OCTN2对米屈肼和氘代左旋肉碱的摄取,半数抑制浓度分别为8.7μmol·L^(-1)和14.0μmol·L^(–1)。孕酮给药组小鼠血清孕酮浓度为462~1153 nmol·L^(-1),与妊娠晚期生理浓度相当,左旋肉碱的尿液排泄量以及血浆、肝脏、肾脏和心脏中左旋肉碱浓度与对照组无显著差异。结论孕酮显著抑制OCTN2功能,但与妊娠晚期生理浓度相当的孕酮不影响左旋肉碱的肾脏排泄及体内稳态。

五苓散对高尿酸血症小鼠降尿酸及肾保护机制的研究(英文)

目的:研究五苓散对高尿酸血症小鼠降尿酸和肾保护作用并探索其可能的作用机制。方法:在氧嗪酸钾连续7天诱导小鼠产生高尿酸血症模型同时每天灌胃给予不同剂量五苓散(每组10只),并以别嘌呤醇作为阳性药对照。分别测定每组动物血清尿酸、肌酐及尿液尿酸、肌酐等水平并计算其尿酸排泄分数。采用RT-PCR和Westernblot方法分别测定小鼠肾脏尿酸盐重吸收转运体1(mURAT1)、葡萄糖转运体9(mGLUT9)、有机阴离子转运体1(mOAT1)、有机阳离子转运体1和2(mOCT1、mOCT2)及肉毒碱转运体2(mOCTN2)mRNA及蛋白表达水平。结果:与模型组比较,五苓散显著降低高尿酸血症小鼠血清尿酸与肌酐水平,促进尿酸和肌酐排泄,提高尿酸排泄分数,呈现出促进肾脏尿酸排泄与肾保护作用。五苓散显著下调高尿酸血症动物肾脏mURAT1、mGLUT9mRNA及蛋白表达水平,并上调mOAT1、mOCT1、mOCT2以及mOCTN2mRNA及蛋白表达水平。结论:这些结果表明五苓散可介导肾脏有机离子转运体表达以促进高尿酸血症和肾功能异常动物尿酸排泄并发挥其肾保护作用。