齐墩果酸对OATP1B1介导药物转运功能的关联性影响

目的 探讨齐墩果酸对有机阴离子转运多肽1B1（organic anion transporting polypetide1B1,OATP1B1）转运功能的关联性影响。方法 利用稳定表达人OATP1B1的人胚胎肾293（hunan embyonic kindney293,HEK293）细胞株,以氟伐他汀为底物进行OATP1B1摄取反应,观察齐墩果酸对OATP1B1摄取功能的影响。结果 齐墩果酸对OATP1B1摄取氟伐他汀的功能有竞争性抑制作用,抑制常数Ki值为（20.3±2.1）mmol·L^-1。结论 齐墩果酸对肝脏药物转运体OATP1B1转运抑制作用可诱导中西药相互作用。     

山胡椒内生真菌Trichoderma sp. SHJN1和Perenniporia sp. SHJG1的抗肿瘤活性成分研究

目的 从民族药山胡椒内生真菌Trichoderma sp.SHJN1和Perenniporia sp.SHJG1的代谢物中寻找活性先导化合物。方法 采用正相硅胶、反相硅胶、Sephadex LH-20凝胶及制备型HPLC等对Trichoderma sp.SHJN1和Perenniporia sp.SHJG1发酵物进行分离纯化，再通过NMR、ESI-MS等鉴定化合物结构，同时采用人乳腺癌细胞（MCF-7）和人肺癌细胞（A549）对这些化合物的抗肿瘤活性进行初步评价。结果 从2株内生真菌次级代谢产物中共分离鉴定了12个化合物：alantrypinone （1）、oryzalactam （2）、phomoindene A （3）、cis-gregatin B （4）、huaspenone B （5）、stigmasta-7，22-dien-3β，5α，6α-triol （6）、ergosterol （7）、1-deoxy-2-demethylviridiol （8）、viridiol （9）、trichodermamides A （10）、chromone （11）、对-羟基苯乙酸（12）。抗肿瘤活性评价结果显示，化合物3 抑制MCF-7细胞增殖活性IC₅₀为（62.9±1.02）μmol·L^-1[顺铂（cisplatin，DDP） IC₅₀为（30.1±1.67）μmol·L^-1]；化合物8 和9 抑制A549细胞增殖活性的IC₅₀分别为（34.6±1.57）μmol·L^-1和（44.9±1.74）μmol·L^-1[DDP IC₅₀为（20.6±1.42）μmol·L^-1]。结论 化合物3 ，8 和9 具有潜在抗肿瘤活性。     

乌骨藤中C21甾体苷诱导SACC-83和SACC-LM细胞凋亡的作用及其机制研究

目的 研究乌骨藤提取物C₂₁甾体苷对唾液腺腺样囊性癌（salivary adenoid cystic carcinomacv,SACC）低侵袭细胞株（salivary adenoid cystic carcinoma-83,SACC-83）和肺高转移细胞株（SACC-LM）增殖抑制和诱导凋亡的作用及其机制。方法 用不同浓度（5,10,20,40,60,80,100 μmol·L^-1） C₂₁甾体苷处理SACC-83和SACC-LM细胞48 h后,MTT法检测细胞活力,并计算药物的IC₂₀和IC₅₀;细胞克隆形成实验检测细胞增殖能力;流式细胞术检测SACC-83及SACC-LM细胞凋亡情况;实时荧光定量PCR和Western blot检测SACC-83和SACC-LM细胞Bcl-2、Bax、caspase 3的mRNA和蛋白的表达。结果 不同浓度的C₂₁甾体苷降低SACC-83和SACC-LM细胞活力,抑制细胞增殖,并且作用于SACC-83细胞C₂₁甾体苷的IC₂₀浓度为7.49 μmol·L^-1,IC₅₀浓度为38.34 μmol·L^-1;作用于SACC-LM细胞的C₂₁甾体苷IC₂₀浓度为9.30 μmol·L^-1,IC₅₀浓度为46.04 μmol·L^-1;细胞克隆集落形成明显减少。C₂₁甾体苷IC₂₀浓度分别促进SACC-83及SACC-LM细胞凋亡,且随着给药时间延长,凋亡率增加,具有显著性差异（P<0.05,P<0.01）。经7.49,9.30 μmol·L^-1 C₂₁甾体苷分别处理SACC-83及SACC-LM细胞后,Bcl-2的mRNA及蛋白水平显著降低（P<0.01）,而Bax、Caspase 3的mRNA和蛋白水平显著升高（P<0.05）。结论 乌骨藤C₂₁甾体苷抑制SACC-83及SACC-LM细胞增殖、促进凋亡,其作用机制可能与调控Bcl-2、Bax和Caspase 3表达有关。     

二茂铁杂环类化合物的合成及抗三阴性乳腺癌活性研究

目的 设计、合成杂环二茂铁衍生物,并研究其抗三阴性乳腺癌活性。方法 以二茂铁查耳酮为先导化合物,对其进行结构改造,合成了一系列含有杂环的二茂铁衍生物,并通过CCK8试剂盒测试化合物抗乳腺癌活性。结果 合成了28个二茂铁衍生物,其结构均通过¹H-NMR和MS加以确证。初步的生物活性测试结果表明,所合成的二茂铁衍生物对三阴性乳腺癌MDA-MB-231细胞有较强的选择性和抑制活性,其中咪唑杂环化合物抗肿瘤活性强于相应的吡唑类和嘧啶化合物。尤其是28a[IC₅₀=（1.6±0.23）μmol·L^-1]对MDA-MB-231的抑制活性分别是先导化合物3[IC₅₀=（10.7±1.41）μmol·L^-1]和他莫昔芬[IC₅₀=（13.7±1.17）μmol·L^-1]的6和10倍,同时这些二茂铁衍生物对正常乳腺上皮细胞MCF-10A均没有毒性。结论 本研究为开发具有抗三阴性乳腺癌活性的化合物提供了信息和依据。     

2',4'-二羟基-3'-甲基-3-甲氧基查耳酮上调p21抑制人肝癌HepG2细胞的生长

目的 探讨2'',4''-二羟基-3''-甲基-3-甲氧基查耳酮(C20)对人肝癌HepG2细胞的体外抗肿瘤作用及其潜在的作用机制。方法 通过CCK-8法、集落形成实验、5-乙炔基-2''-脱氧尿苷(EdU)染色法检测C20对人肝癌HepG2细胞增殖的影响;通过彗星实验检测C20(10 μmol·L^-1)对HepG2细胞DNA损伤的影响;通过流式细胞术检测C20(5、10 μmol·L^-1)对HepG2细胞周期阻滞的影响;通过Hoechst染色和流式细胞术检测C20(5、10 μmol·L^-1)对HepG2细胞凋亡的影响。借助Western blotting法检测C20(5、10 μmol·L^-1)处理对HepG2细胞中与凋亡、DNA损伤、细胞周期阻滞相关蛋白表达水平的调控作用。结果 与对照组比较,C20显著抑制HepG2细胞的活力(P<0.001),给药48 h的半数抑制浓度(IC₅₀)为7.937 μmol·L^-1;5 μmol·L^-1 C20能够显著抑制HepG2细胞的集落形成能力(P<0.01);EdU染色结果显示5、10 μmol·L^-1的C20能够抑制人肝癌HepG2细胞的增殖能力;5、10 μmol·L^-1的C20显著诱导HepG2细胞G₂/M期阻滞(P<0.001);5、10 μmol·L^-1的C20显著促进HepG2细胞凋亡(P<0.001),并显著上调Caspas-3、Caspase-9以及PARP的剪切水平(P<0.01);10 μmol·L^-1的C20能够诱导HepG2细胞发生DNA损伤,并且5、10 μmol·L^-1的C20显著上调γH2AX、p21的蛋白水平(P<0.01)。结论 C20能够造成HepG2细胞发生DNA损伤,上调p21蛋白水平,导致细胞G₂/M期阻滞,并进一步诱发凋亡,发挥体外抗肝癌作用。     

芫花主要黄酮成分对肝微粒体UGTs及UGT1A1活性的体外抑制作用

目的 考察芫花主要黄酮成分芫花素和芹菜素对尿苷二磷酸葡萄糖醛酸转移酶（UGTs）及UGT1A1活性的影响。方法 采用体外肝微粒体孵育模型,以4-硝基酚（4-nitrophenol,4-NP）为底物检测UGTs活性,胆红素为底物检测UGT1A1活性;利用UV及UPLC-MS/MS测定底物或代谢产物的含量。结果 对UGTs,在大鼠肝微粒体、小鼠肝微粒体以及人肝微粒体孵育体系中,芫花素和芹菜素均能不同程度地抑制UTGs活性;抑制强弱顺序：在大鼠肝微粒体温孵体系中,芫花素>芹菜素;在小鼠肝微粒体以及人肝微粒体温孵体系中,芹菜素>芫花素。对UGT1A1,在人肝微粒体孵育体系中,芫花素和芹菜素均表现为中等强度的竞争性抑制作用,抑制强弱顺序：芹菜素（IC₅₀=12.40 μmol·L^-1）>芫花素（IC₅₀=23.21 μmol·L^-1）。结论 芫花素和芹菜素对不同肝微粒体孵育体系中UGTs及UGT1A1均可产生显著抑制作用且存在种属差异。芫花素及芹菜素可能存在基于UGT酶的药物相互作用。     

一种新型多环螺环氧化吲哚类化合物对肺癌细胞系的生长抑制作用及其机制

目的 探究一种新型多环螺环氧化吲哚化合物对肺细胞系生长抑制的作用与机制。方法 首先通过MTT试验、流式细胞技术与细胞划痕试验检测化合物对肺癌细胞系的增殖、细胞凋亡以及细胞迁移的影响。接着通过PharmMapper平台预测其靶标蛋白,通过GEPIA平台预测与该靶蛋白具有较强相关性的蛋白,最后分别通过双荧光素酶报告基因试验,qPCR试验以及免疫印迹试验,在启动子水平、转录水平和表达水平检测化合物对目的基因的影响。结果 实验结果表明化合物能够显著抑制SKLU1细胞系的增殖,IC₅₀值为11.38 μmol·L^-1,化合物浓度>2.85 μmol·L^-1即能够抑制SKLU1的细胞迁移,浓度>5.69 μmol·L^-1能够诱导细胞凋亡。其分子机理可能是通过靶向RhoGEF7蛋白,下调下游的Rac1蛋白表达量,从而下调E-cadherin蛋白表达量,抑制细胞迁移;并且,下调的Rac1蛋白还能抑制NF-κB的激活,下调下游基因IL-6和IL-8的转录;下调的Rac1蛋白还能抑制IL-6/JAK/STAT3通路。结论 本研究为这种新型多环螺环氧化吲哚化合物靶向肺癌细胞的分子机制提供理论依据。     

细胞色素P450介导的氯沙坦钾对瑞格列奈在大鼠肝微粒体中代谢的影响

目的 研究瑞格列奈在大鼠肝微粒体中的酶促反应动力学，并考察氯沙坦钾对其在大鼠肝微粒体中代谢的影响。方法 建立大鼠肝微粒体体外孵育体系对瑞格列奈的代谢进行研究；以洛伐他汀为内标，应用UPLC测定大鼠肝微粒体中瑞格列奈的浓度。采用底物减少法，通过GraphPad Prism 5.0软件计算瑞格列奈的酶促反应动力学常数V_max和K_m；分别以系列浓度氯沙坦钾（2.5~50μmol·L^-1）与瑞格列奈（44 μmol·L^-1）于37℃水浴中共同孵育，并测定肝微粒体中瑞格列奈的减少量，考察氯沙坦钾对瑞格列奈的抑制作用。结果 瑞格列奈在大鼠肝微粒体的最佳孵育时间为40 min，最佳蛋白质量浓度为1 mg·mL^-1；瑞格列奈酶促反应动力学参数V_max=47.29μmol·min^-1·（mg·protein）^-1，K_m=51.41 μmol·L^-1；氯沙坦钾对瑞格列奈在体外肝微粒体抑制作用的IC₅₀值为17.89 μmol·L^-1。结论 氯沙坦钾对瑞格列奈在大鼠肝微粒体中的代谢具有较强的抑制作用，两药联合应用可能发生相互作用，具有诱发低血糖的风险。     

淫羊藿苷元对临床重要药物转运体抑制作用研究

目的 研究淫羊藿苷元对临床重要转运体OAT1、OAT3、OATP1B1、OATP1B3、OCT1、OCT2、BCRP、BSEP和P-gp转运蛋白的抑制作用。方法 应用过表达各转运体的细胞株,检测淫羊藿苷元（0、0.03、0.10、0.30、1.00、3.00、10.00 μmol/L）对hOAT1介导的放射性同位素标记底物¹⁴C-对氨基马尿酸（¹⁴C-PAH）、hOAT3介导的³H-硫酸雌酮铵（³H-ES）、hOATP1B1介导的³H-ES、hOATP1B3介导的³H-雌二醇葡糖苷酸（³H-EG）、hOCT1介导的¹⁴C-溴化四乙胺（¹⁴C-TEA）、hOCT2介导的¹⁴C-TEA、hBCRP介导的³H-ES、MDR1介导的³H-地高辛（³H-Digoxin）、以及hBSEP介导的³H-牛黄胆酸盐（³H-TCA）转运活性的影响,计算淫羊藿苷元对不同转运蛋白的抑制作用的半数抑制浓度（IC₅₀）。结果 与对照组比较,淫羊藿苷元0.3～10 μmol/L浓度对OAT3转运活性发挥显著抑制作用（P<0.05）,0.1～10 μmol/L对P-gp有显著抑制作用;1～10 μmol/L浓度对OATP1B3和BCRP转运活性有显著抑制作用（P<0.05）;3～10 μmol/L浓度对和OATP1B1转运活性有显著抑制作用（P<0.05）;对OAT3和BCRP转运活性的IC₅₀分别为4.97和8.15 μmol/L;对OAT1B1、OATP1B3、OCT2和P-gp的IC₅₀均大于10 μmol/L,对OAT1、OCT1和BSEP转运活性无明显影响。结论 淫羊藿苷元对药物转运体OAT3和BCRP的抑制作用相对较强,对OAT1B1、OATP1B3、OCT2和P-gp也具有一定的抑制作用,对OAT1、OCT1和BSEP无显著抑制作用。     

头孢克洛分散片中聚合物测定

目的 建立2种头孢克洛聚合物有效的测定方法并对结果进行比较。方法 方法1：采用TSKgel G2000SWxl色谱柱（7.8 mm×300 mm,5 μm）,流动相为0.01 mol·L^-1磷酸盐缓冲液[0.01 mol·L^-1 NaH₂PO₄溶液-0.01 mol·L^-1 Na₂HPO₄溶液（50︰50）,调节pH值为7.0]-乙腈（95︰5）,流速为0.5 mL·min^-1柱温35℃,检测波长为254 nm,进样量20 μL;方法2：采用Sephadex G-10色谱柱（10 mm×300 mm,40~120 μm）,以0.05 mol·L^-1磷酸盐缓冲液[取0.05 mol·L^-1 Na₂HPO₄溶液-0.05 mol·L^-1 NaH₂PO₄溶液（50︰50）,调节pH至7.0]为流动相A,水为流动相B,流速为1 mL·min^-1,柱温35℃,检测波长为254 nm,进样量100 μL。结果 方法1：头孢克洛主峰与聚合物峰分离度>1.5,头孢克洛质量浓度在0.25~20 μg·mL^-1内线性关系良好（r=0.999 9）;定量限0.21 μg,检测限0.07 μg。重复性较好（RSD为1.8%,n=6）;在拟定的色谱条件下,通过考察破坏坏性实验（高温、强酸、强碱、氧化、光照）能够满足分离度要求,辅料无干扰;方法2：质量浓度在2.5~20 μg·mL^-1线性关系良好（r=0.999 7）;检测限0.13 μg,定量限0.40 μg。重复性良好（RSD为1.8%,n=6）。结论 新建立的2种方法对于头孢克洛分散片聚合物的分离度好,分离效率高,重复性好,均可以作为头孢克洛分散片的质量控制的依据。     

有机阴离子转运多肽1B1的遗传药理学进展

人体存在多种类型的药物转运体,对于药物的吸收、分布和排泄起重要作用。参与药物跨膜转运的转运体功能受影响,将可能导致诸多临床药物的疗效、毒副作用甚至药物相互作用的发生。在各种影响因素中,遗传多态性所起的作用最为重要,可导致基因表达和蛋白功能发生改变。目前,阐明转运体基因的多态性以及基因型与表型之间的相互关系已成为应用遗传信息指导临床个体化用药的必要步骤。本文就肝脏有机阴离子转运多肽1B1（OATP1B1[OATP-C],编码基因SLCO1B1）基因多态性对药代动力学和药效动力学的影响及其临床意义等方面的进展作一综述。     

Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3.

The serine/threonine protein phosphatase (PP) 2A inhibitor, microcystin-LR, selectively induces liver damage and promotes hepatocarcinogenesis. It is thought that microcystin-LR affects hepatocellular viability mainly through inhibition of PP2A, partially through PP1, and, in addition, by generation of reactive oxygen species (ROS). However, the molecular basis of the selective liver damage and the balance between cell death and survival remained unclear. We analyzed the cytotoxicity of low doses of microcystin-LR using HEK293 cells stably expressing the human hepatocyte uptake transporters, organic anion transporting polypeptide (OATP)1B1 (HEK293-OATP1B1 cells) and OATP1B3 (HEK293-OATP1B3 cells). HEK293-OATP1B1 (IC(50) 6.6nM) and HEK293-OATP1B3 cells (IC(50) 6.5nM) were equally very sensitive to microcystin-LR. In contrast, control-vector-transfected (HEK293-CV) cells were resistant to microcystin-LR. Using HEK293-OATP1B3 cells, the cytotoxicity was attenuated by substrates and inhibitors of OATP1B3, including bromosulfophthalein, rifampicin, and cyclosporin A. Microcystin-LR was transported into HEK293-OATP1B3 cells with 1.2 microM Km value, and its uptake was inhibited by above substances. Accumulation of microcystin-LR in the HEK293-OATP1B1 and HEK293-OATP1B3 cells was increased in a dose-dependent manner but not in HEK293-CV cells. Cellular serine/threonine PP activity of HEK293-OATP1B3 cells was decreased by microcystin-LR but not in HEK293-CV cells. Apoptotic changes were observed after incubation of the HEK293-OATP1B3 cells with microcystin-LR. We found by FACS analysis that microcystin-LR induced apoptosis but not necrosis in HEK293-OATP1B3 cells. Microcystin-LR activated several mitogen-activated protein kinases (MAPKs) including ERK1/2, JNK, and p38 through inhibition of PP2A. In addition, the cytotoxicity of microcystin-LR was attenuated by the inhibitors of MAPK pathways, including U0126, SP600125, and SB203580. The ROS scavenger N-acetyl-L-cysteine partially attenuated the cytotoxicity of microcystin-LR. Thus, the present study demonstrates that microcystin-LR induces apoptosis through activation of multiple MAPK pathways subsequent to its selective uptake via OATP1B1 and OATP1B3 and followed by inhibition of PP2A, in addition to the ROS generation which might contribute to apoptosis.     

Modulation of transporter activity of OATP1B1 and OATP1B3 by the major active components of Radix Ophiopogonis

Abstract

1. Radix Ophiopogonis is often an integral part of many traditional Chinese formulas, such as Shenmai injection used to treat cardio-cerebrovascular diseases. This study aimed to investigate the influence of the four active components of Radix Ophiopogonis on the transport activity of OATP1B1 and OATP1B3.

2. The uptake of rosuvastatin in OATP1B1-HEK293T cells were stimulated by methylophiopogonanone A (MA) and ophiopogonin D′ (OPD′) with EC₅₀ calculated to be 11.33?±?2.78 and 4.62?±?0.64?μM, respectively. However, there were no remarkable influences on rosuvastatin uptake in the presence of methylophiopogonanone B (MB) or ophiopogonin D (OPD). The uptake of atorvastatin in OATP1B1-HEK293T cells can be increased by MA, MB, OPD and OPD′ with EC₅₀ calculated to be 6.00?±?1.60, 13.64?±?4.07, 10.41?±?1.28 and 3.68?±?0.85?μM, respectively.

3. The uptake of rosuvastatin in OATP1B3-HEK293T cells was scarcely influenced by MA, MB and OPD, but was considerably increased by OPD′ with an EC₅₀ of 14.95?±?1.62?μM. However, the uptake of telmisartan in OATP1B3-HEK293T cells was notably reduced by OPD′ with an IC₅₀ of 4.44?±?1.10?μM, and barely affected by MA, MB and OPD.

4. The four active components of Radix Ophiopogonis affect the transporting activitives of OATP1B1 and OATP1B3 in a substrate-dependent manner.

     

Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug-drug interactions via these transporters

Objectives We have investigated the contributions of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to the hepatic uptake of nateglinide, and the possibility of drug–drug interactions via these transporters. Methods Uptake studies using transporter‐expressing HEK293 cells and cryopreserved human hepatocytes were performed to examine the contributions of each transporter. Inhibition studies using cryopreserved human hepatocytes were performed to examine the possibility of drug–drug interactions. Key findings The rate of saturable hepatic uptake of nateglinide using human hepatocytes was 47.6%. A certain increase in uptake was observed in the examination using transporter‐expressing HEK293 cells, indicating contributions of OATP1B1 and OATP1B3 to hepatic nateglinide uptake. The 50% inhibitory concentration (IC50) values of nateglinide using cryopreserved human hepatocytes for uptake of estrone 3‐sulfate (substrate of OATP1B1), and cholecystokinin octapeptide (substrate of OATP1B3) were 168 and 17.4 µmol/l, respectively. Moreover, ciclosporin inhibited saturable hepatic uptake of nateglinide with an IC50 value of 6.05 µmol/l. The calculated 1 + I_in,max,u/IC50 values for inhibition of OATP1B1 and OATP1B3 by nateglinide, and the inhibition of saturable uptake of nateglinide by ciclosporin, were all close to 1, indicating a low clinical risk of drug–drug interaction with nateglinide taken up via OATP1B1 and OATP1B3. Conclusions OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug–drug interactions appeared to be low.     

Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes

AIMS: Our aim was to investigate associations between the single nucleotide polymorphisms (SNPs) in the SLCO1B1 (encoding OATP1B1) and ABCB1 (encoding P-glycoprotein) genes with the pharmacokinetics and efficacy of pravastatin in children with heterozygous familial hypercholesterolaemia (HeFH) and in paediatric cardiac transplant recipients. METHODS: Twenty children with HeFH (aged 4.9-15.6 years) and 12 cardiac transplant recipients (aged 4.4-18.7 years and receiving triple immunosuppressive medication) who had participated in previous pharmacokinetic and pharmacodynamic studies with pravastatin were genotyped for the -11187G > A and 521T > C SNPs in the SLCO1B1 gene and for the 2677G > T/A and 3435C > T SNPs in the ABCB1 gene. RESULTS: Two HeFH patients with the -11187GA genotype had a 81% lower peak plasma pravastatin concentration (Cmax) (difference in means -13.9 ng ml(-1), 95% CI -21.1, -6.7; P < 0.001) and a 74% smaller area under the plasma concentration-time curve (AUC0, infinity) (-25.3 ng ml(-1) h, 95% CI -35.6, -15.0; P < 0.0001) and significantly greater increase in high density lipoprotein (HDL) cholesterol after 2 months treatment with pravastatin than patients with the reference genotype. No significant differences were seen in the pharmacokinetics or effects of pravastatin between HeFH patients with the SLCO1B1 521TC and 521TT genotypes. The cardiac transplant recipients with the SLCO1B1 521TC genotype (n = 3) had a 46% lower Cmax (-67.7 ng ml(-1), 95% CI -135.7, 0.3; P = 0.055) and 62% lower AUC(0,24 h) (-228.5 ng ml(-1) h, 95% CI -402.7, -54.3; P = 0.016) and a shorter half-life (t1/2) (0.9 +/- 0.1 vs. 1.3 +/- 0.4 h, P = 0.015) of pravastatin than those with the reference genotype. Decreases in total and low-density lipoprotein cholesterol by pravastatin were significantly smaller, and the increase in HDL-cholesterol was greater in the transplant recipients with the 521TC genotype compared with patients with the 521TT reference genotype. CONCLUSIONS: In children with HeFH and in paediatric cardiac transplant recipients receiving immunosuppressive medication, the -11187G > A and SLCO1B1 521T > C SNPs were associated with decreased plasma concentrations of pravastatin. These differences are opposite to those seen previously in healthy adults. The mechanisms underlying these phenomena are unclear and warrant further study.     

HMG—CoA还原酶抑制药与转运体OATP1B1

长期以来药物代谢一直被认为是药物分布过程中的主要决定因素。然而，近年来的研究不断证实膜转运体也具有同样重要的作用。事实上，许多外向转运体如MDR1基因编码的P糖蛋白在药物体内分布和药物效应方面的作用已被广泛而深入的加以研究。一些药物在胃肠道、肝和肾脏等许多器官的定向运动中需要内向和外向转运体来协调转运。例如，在外向转运体介导的药物代谢和经胆道排泄之前，分布在肝细胞基底膜上的内向转运体一一有机阴离子转运体超家族（organic anio-transporting polypeptides，OATPs），可促进药物在细胞内集聚。     

No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone

AIMS

To examine possible effects of polymorphism in the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, on the pharmacokinetics of rosiglitazone and pioglitazone in a prospective genotype panel study.

METHODS

Sixteen healthy volunteers with the homozygous SLCO1B1 c.521TT genotype (controls), 12 with the heterozygous c.521TC genotype and four with the homozygous c.521CC genotype ingested a single 4-mg dose of rosiglitazone and a single 15-mg dose of pioglitazone in a cross-over study with a wash-out period of at least 1 week.

RESULTS

SLCO1B1 polymorphism had no statistically significant effect on any of the pharmacokinetic variables of rosiglitazone, pioglitazone or their metabolites. The mean ± SD area under the plasma rosiglitazone concentration–time curve from time 0 to infinity (AUC_0–∞) was 2024 ± 561 ng ml⁻¹ h in the c.521TT subjects, 1763 ± 288 ng ml⁻¹ h in the c.521TC subjects (geometric mean ratio c.521TC/c.521TT 0.89; 95% confidence interval 0.72, 1.11) and 1729 ± 346 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.87; 0.63, 1.20). The AUC_0–∞ of pioglitazone averaged 6244 ± 1909 ng ml⁻¹ h in the c.521TT subjects, 5123 ± 1165 ng ml⁻¹ h in the c.521TC subjects (c.521TC/c.521TT 0.83; 0.65, 1.06) and 4851 ± 1123 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.79; 0.55, 1.14). There was a significant correlation between the AUC_0–∞ of rosiglitazone and pioglitazone (r = 0.717, P < 0.001).

CONCLUSIONS

The SLCO1B1 c.521T→C SNP does not affect the pharmacokinetics of rosiglitazone or pioglitazone, indicating that OATP1B1 plays no significant role in the disposition of these drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• A common single nucleotide polymorphism (SNP) (c.521T→C) of the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, has been associated with marked changes in the pharmacokinetics of the antidiabetic drug repaglinide.
• Rosiglitazone and pioglitazone are competitive inhibitors of OATP1B1 and might thus be its substrates.
• Gemfibrozil, an inhibitor of OATP1B1 in vitro, considerably increases the plasma concentrations of rosiglitazone and pioglitazone in vivo in humans.

WHAT THIS STUDY ADDS

• The SLCO1B1 c.521T→C SNP was not associated with changes in rosiglitazone or pioglitazone pharmacokinetics in healthy volunteers.
• OATP1B1 is thus unlikely to play an important role in the disposition of rosiglitazone or pioglitazone.

     

Alteration of the intravenous and oral pharmacokinetics of valsartan via the concurrent use of gemfibrozil in rats

The present study aimed to examine the potential pharmacokinetic drug interaction between valsartan and gemfibrozil. Compared with the control given valsartan (10 mg/kg) alone, the concurrent use of gemfibrozil (10 mg/kg) significantly (p < 0.05) increased the oral exposure of valsartan in rats. In the presence of gemfibrozil, the C_max and AUC of oral valsartan increased by 1.7‐ and 2.5‐fold, respectively. Consequently, the oral bioavailability of valsartan was significantly higher (p < 0.05) in the presence of gemfibrozil compared with that of the control group. Furthermore, the intravenous pharmacokinetics of valsartan (1 mg/kg) was also altered by pretreatment with oral gemfibrozil (10 mg/kg). The plasma clearance of valsartan was decreased by two‐fold in the presence of gemfibrozil, while the plasma half‐life was not altered. In contrast, both the oral and intravenous pharmacokinetics of gemfibrozil were not affected by the concurrent use of valsartan. The cellular uptake of valsartan and gemfibrozil was also investigated by using cells overexpressing OATP1B1 or OATP1B3. Gemfibrozil and gemfibrozil 1‐O‐β glucuronide inhibited the cellular uptake of valsartan with IC₅₀ values (µm ) of 39.3 and 20.4, respectively, in MDCK/OATP1B1, while they were less interactive with OATP1B3. The cellular uptake of gemfibrozil was not affected by co‐incubation with valsartan in both cells. Taken together, the present study suggests the potential drug interaction between valsartan and gemfibrozil, at least in part, via the OATP1B1‐mediated transport pathways during hepatic uptake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.