Caco-2细胞对酸枣仁皂苷A的跨膜转运

目的研究酸枣仁皂苷A（Jujuboside A,JuA）在Caco-2细胞的跨膜转运特性。方法采用体外培养的Caco-2细胞单层模型,考察时间、介质pH值、药物浓度、抑制剂对JuA在Caco-2细胞上转运的影响。结果 Caco-2细胞转运JuA呈时间及浓度依赖性;在pH为5.0～8.0范围内,Caco-2细胞对JuA的转运不受pH值的影响;P-糖蛋白（P-glycoprotein,P-gp）抑制剂维拉帕米（Verapamil,Ver）对Caco-2细胞转运JuA无影响;线粒体呼吸链复合体Ⅳ抑制剂叠氮化钠（Sodium azide）对Caco-2细胞转运JuA有抑制作用;JuA的AP-BL侧的Papp与BL-AP侧的Papp的两组均数比较无统计学意义。结论 JuA不是P-gp的底物,其跨膜转运是被动转运与主动转运共同参与的过程。     

P-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响

目的 研究Caco-2细胞模型中P-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响.方法 采用HPLC法测定转运液中蝙蝠葛碱的含量;采用Caco-2细胞模型双向转运实验,考察不同浓度维拉帕米、环孢素A和醋酸地塞米松3种p-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响.结果 加入3种P-糖蛋白抑制剂后,蝙蝠葛碱的Papp(A-B)均有一定程度增加,而Papp(B-A)均有显著降低(P＜0.05),即均抑制了蝙蝠葛碱的外排转运.结论 外排转运体P-糖蛋白对蝙蝠葛碱有外排作用,蝙蝠葛碱可能为P-糖蛋白底物.     

仙茅苷在Caco-2细胞模型中跨膜转运特征研究

目的：采用Caco-2细胞Transwell模型研究仙茅苷的跨膜转运机制。方法：建立Caco-2细胞Transwell吸收模型,用聚酯碳酸酯膜培养Caco-2细胞21天,形成致密的单层细胞模型。研究浓度、时间、温度、细胞旁路转运及跨膜转运蛋白（P-糖蛋白,多药耐药蛋白,乳腺癌耐药蛋白）在仙茅苷跨膜转运中的作用。结果：仙茅苷在Caco-2细胞模型中的跨膜转运存在一定的浓度及时间依赖性,细胞旁路转运不参与其转运,仙茅苷的外排转运存在一定的能量依赖性,且由P-gp参与。结论：仙茅苷在Caco-2细胞模型上主要以主动转运方式作跨膜转运,且P-gp参与其跨膜转运。     

9-硝基喜树碱在Caco-2细胞模型中的体外摄取、转运及外排动力学

目的研究9-硝基喜树碱(9-NC)的细胞摄取、转运及外排特性。方法一种体外培养的人小肠上皮细胞模型Caco-2应用于9-NC的小肠上皮细胞的摄取、跨膜转运及外排动力学研究。评价了时间、温度、pH,P-糖蛋白(P-glycoprotein, P-gp)抑制剂对细胞摄取的影响。采用HPLC测定药物含量。结果9-硝基喜树碱以被动扩散为主要方式被细胞摄取和转运。药物的摄取与时间呈正相关，与温度、pH呈负相关。P-gp抑制剂环孢菌素和维拉帕米增加9-NC细胞摄取(P<0.05)。药物从Basolateral(B,基底面)到Apical(A,肠腔面)的渗透系数P_app大于A到B(2.6-6.9倍)。9-NC外排符合二级外排动力学过程，A侧m₀［(148.0±2.2) pmol·cm^-2］和外排速率(41.1 pmol·cm²·min^-1)高于B侧的m₀［(121±7) pmol·cm^-2(P<0.05)和外排速率(29.2 pmol·cm²·min^-1)(P<0.01)。结论 9-NC是以被动扩散方式为主要方式被小肠上皮细胞摄取和转运，并受到P-糖蛋白强烈的外排作用。     

新抗癌活性物AG337在Caco-2细胞模型中经p-糖蛋白介导的跨细胞转运

目的研究AG337在Caco-2细胞模型中的转运机制.方法改变药物浓度和实验温度以及他用合适抑制剂,测定AG337的跨细胞转运速率及其在细胞内的累积量.结果AG337的跨细胞转运显示强烈的有向性,B→A转运(细胞绒毛而Apical→基底面Basolateral)大于A→B10倍以上,P-糖蛋白的专属抑制剂维拉帕米(Ver)可以消除这种有向性温度从37℃至4℃时B→A的转运速率下降50倍,而A→B下降不大.结论AG337在Caco-2模型中的跨细胞转运.受到P-糖蛋白强烈的外排作用.     

蛇床子素及其制剂在Caco-2细胞模型中转运机制的研究

I摘要】目的：研究蛇床子素及其制剂在Caco-2细胞模型中的摄取、转运机制。方法：建立Caco-2细胞单层模型,研究蛇床子素、蛇床予素β-环糊精包合物及其包合物分散片的摄取和跨膜转运,考察其时间、温度、浓度、吸收促进剂和抑制剂对药物摄取及跨膜吸收的影响,并比较原料药与制剂吸收过程的差异。结果：Caco-2细胞对蛇床子素及其制剂溶液的摄取与时间、温度、浓度均呈正相关,p-糖蛋白抑制剂（CyA）与能量抑制剂（NaN3）对摄取无显著性影响,其摄取量的大小依次为分散片〉包合物〉原料药;转运实验中,随浓度和温度的增加,蛇床子素及其制刑的溶液在Caco-2细胞中的转运量均增加,而只r与Rt比值无明显变化,P-糖蛋白抑制剂（CyA）、能量抑制剂（NaN,）、细胞内吞抑制剂．氧化苯砷（oxophenylarsine）7L胞旁路转运促进剂一去氧胆酸钠（sodiumdeoxycholate,SDCh）对蛇床子素的转运无影响,而去氧胆酸钠对包合物和分散片的转运有明显的影响,3种制刑AP—BL方向上的Papp为分散片〉包合物〉原料药。结论：蛇床子素主要以被动扩散的方式被吸收,包合物和分散片中的药物以被动转运为主,少部分以细胞旁路转运途径被细胞吸收;难溶性药物经包合物可促进其吸收,制剂辅料对药物的吸收有一定的促进作用。     

LC-MS测定雷公藤甲素及其在Caco-2细胞上的转运特征

目的：建立体外模拟体内肠道细胞的Caco-2细胞Transwell模型,以此研究雷公藤甲素在Caco-2细胞模型上的跨膜转运特征。方法：采用聚酯碳酸酯膜连续培养Caco-2细胞21天,形成致密的单层细胞模型。然后对影响雷公藤甲素在Caco-2细胞模型上转运特征的因素包括浓度、时间及跨膜转运蛋白（P-糖蛋白,多药耐药蛋白,乳腺癌耐药蛋白）进行考察;同时采用LC-MS对溶液中的雷公藤甲素的含量进行测定。结果：雷公藤甲素主要以主动转运的方式进行吸收,且随着时间和药物浓度的增加,转运量明显增加。结论：雷公藤甲素在Caco-2细胞上转运存在一定的浓度及时间依赖性,且P-gp介导雷公藤甲素在Caco-2细胞上转运。     

5-氟尿嘧啶在Caco-2细胞模型中的吸收特性

为研究5-氟尿嘧啶(5-FU)在Caco-2细胞模型中的吸收特性,用Caco-2细胞模型,分别测定了在各种条件下对5-FU的吸收。结果显示:吸收在pH6的介质中为佳;吸收的初速随浓度的增加趋于一个饱和值,Michaelis常数K_m=24mmol·L^-1;吸收可被氰化钠、哇巴因、双嘧达莫等代谢抑制剂抑制,也被同类结构的化合物尿嘧啶、胸腺嘧啶、尿核苷等抑制。由此可知,5-FU的吸收可由尿嘧啶载体转运。     

P-糖蛋白对番荔枝酰胺衍生物FLZ在Caco-2细胞模型中跨膜转运的影响

目的考察转运蛋白P-糖蛋白(P-glycoprotein,P-gp)对番荔枝酰胺衍生物FLZ体外跨血脑屏障(Blood-brain barrier,BBB)转运的影响。方法采用体外培养的Caco-2细胞建立体外BBB模型,研究1,5,10μM FLZ跨膜转运特性。并探讨加入P-gp抑制剂5μM zosuquidar后FLZ跨膜转运的表观渗透系数和外排率的变化。结果 FLZ在Caco-2细胞模型上显示出了极性转运特性,Papp(B~A)>Papp(A~B),并呈现出良好的剂量依赖关系。同时FLZ在Caco-2细胞的跨膜转运中也呈现外排现象,1,5,10μM FLZ的外排率ER值分别为2.56,3.67和5.06。P-gp抑制剂zosuquidar可以显著降低FLZ外排,增加转运。10μM FLZ的外排率由5.06降低为1.94,下降了2.6倍。结论 FLZ具有P-gp的底物特性,P-gp参与了FLZ在BBB跨膜转运中的外排。     

5-氨基水杨酸在Caco-2、L-MDR1和MRP2细胞中的转运研究

目的:研究5-氨基水杨酸(5-ASA)的跨膜转运是否涉及P-糖蛋白和多药耐药蛋白(MRP2)。方法:以Caco-2、L-MDR1、MRP2等三种细胞为模型,测定5-ASA跨膜转运的转运率和表观渗透常数。此外还研究了5-ASA对地高辛在Caco-2细胞转运的影响。结果:在Caco-2、L-MDR1和MRP2细胞,5、50、500μmol·L-15-ASA从底端(B)→顶端(A)方向和A→B方向的转运率和表观渗透系数(Papp)均无统计学差异(P>0.05)。在Caco-2细胞,与未用5-ASA组相比,各浓度5-ASA组(50μmol·L-1~5mmol·L-1)对地高辛的Papp和B→A方向的净转运率无明显影响(P>0.05)。结论:5-ASA可能不是P-糖蛋白和MRP2的底物,也不能提示5-ASA是P-糖蛋白的抑制剂或诱导剂。     

CYP3A和P-糖蛋白对布格呋喃在大鼠小肠吸收的影响

本研究采用大鼠小肠在体单向 (single-pass) 灌流模型, 收集灌流后不同时间点灌流液和肠系膜静脉血, 应用GC-MS联用法测定灌注液和血浆中的布格呋喃含量, 并计算布格呋喃渗透系数［P_lumen = −(Q/2πrl) Ln(C_out/C_in) 和P_blood = (ΔM_B/Δt)/(2πrl)］, 从而反映布格呋喃的代谢变化。同时, 观察CYP3A选择性抑制剂醋竹桃霉素 (TAO)、CYP3A和P-糖蛋白 (P-gp) 共同抑制剂环孢素A (CsA) 和P-gp选择性抑制剂LSN335984对布格呋喃自大鼠肠道吸收的影响。结果表明, 在大鼠小肠在体单向灌流模型中加入LSN335984、TAO和CsA后, 大鼠肠系膜静脉血中布格呋喃的累积量分别为73.4、82.9和98.3 pmol·cm⁻², 与对照组比较分别增加3.9倍、4.6倍和5.6倍, 代谢分别减少12%、11%和21%。提示CYP3A和P-gp选择性抑制剂可明显减少布格呋喃在大鼠肠道的首过效应, 促进布格呋喃的肠道吸收。由此可见, P-gp与CYP3A两者联合作用是引起布格呋喃口服生物利用度低的重要因素, 两者对布格呋喃小肠吸收均具有重要影响。     

Biopharmaceutics classification and intestinal absorption of chikusetsusaponin IVa

The objective of this study was to investigate the absorption behavior of chikusetsusaponin IVa (CHS‐IVa) in the rat intestine using single‐pass intestinal perfusion (SPIP) and to classify CHS‐IVa into the biopharmaceutics classification system (BCS). The equilibrium solubility of CHS‐IVa was determined by the shaker method. The absorption mechanism of CHS‐IVa in the intestine was studied by comparing the P_eff of different concentrations of CHS‐IVa. The intestinal site dependence of CHS‐IVa absorption was studied by comparing the P_eff of the same concentration of CHS‐IVa in different intestinal segments. The relationship between CHS‐IVa and intestinal efflux protein was studied by perfusion with an efflux protein inhibitor. The permeability of CHS‐IVa was investigated by comparing the P_eff of CHS‐IVa and the reported value. The solubility of CHS‐IVa over the pH range 1.0–7.5 was 14.4 ± 0.29 to 16.9 ± 0.34 mg/ml. The P_eff of CHS‐IVa in the duodenum was 1.76 × 10^?3 to 2.00 × 10^?3 cm/min. The P_eff of CHS‐IVa in the jejunum was 1.26 × 10^?3 to 1.39 × 10^?3 cm/min. The P_eff of CHS‐IVa in the ileum was 1.25 × 10^?3 to 1.31 × 10^?3 cm/min. The P_eff of CHS‐IVa in the colon was 1.02 × 10^?3 to 1.08 × 10^?3 cm/min. There was no statistical difference of the P_eff in the four segments at different CHS‐IVa concentrations. The P_eff of CHS‐IVa (0.07, 0.7 and 7.0 mg/ml) were all notably smaller than the reported P_eff (3.00 × 10^?3 cm/min) in the jejunum. The P_eff of CHS‐IVa was not influenced by verapamil (P‐gp inhibitor), indomethacin (MRP inhibitor) and pantoprazole (BCRP inhibitor). CHS‐IVa was classified as high solubility, low permeability and BCS III. The main absorptive tracts were the upper intestinal tracts and the rank order of intestinal permeability was duodenum > jejunum ≈ ileum > colon. The transport mechanism of CHS‐IVa in all intestinal segments might be primarily passive transport. CHS‐IVa was not a substrate of P‐gp, MRP and BCRP.     

Characterization of loxoprofen transport in Caco‐2 cells: the involvement of a proton‐dependent transport system in the intestinal transport of loxoprofen

Loxoprofen, a propionate non‐steroidal anti‐inflammatory drug (NSAID), is used widely in East Asian countries. However, little is known about the transport mechanisms contributing to its intestinal absorption. The objectives of this study were to characterize the intestinal transport of loxoprofen using the human intestinal Caco‐2 cell model. The transport of loxoprofen was investigated in cellular uptake studies. The uptake of loxoprofen into Caco‐2 cells was pH‐ and concentration‐dependent, and was described by a Michaelis–Menten equation with passive diffusion (K_m: 4.8 mm , V_max: 142 nmol/mg protein/30 s, and K_d: 2.2 μl/mg protein/30 s). Moreover, the uptake of loxoprofen was inhibited by a typical monocarboxylate transporter (MCT) inhibitor as well as by various monocarboxylates. The uptake of [¹⁴C] l ‐lactic acid, a typical MCT substrate, in Caco‐2 cells was saturable with relatively high affinity for MCT. Because loxoprofen inhibited the uptake of [¹⁴C] l ‐lactic acid in a noncompetitive manner, it was unlikely that loxoprofen uptake was mediated by high‐affinity MCT(s). Our results suggest that transport of loxoprofen in Caco‐2 cells is, at least in part, mediated by a proton‐dependent transport system. Copyright © 2016 John Wiley & Sons, Ltd.     

脉君安片中主要成分对氢氯噻嗪在Caco-2细胞模型中转运的影响

利用人源结肠腺癌细胞系Caco-2细胞单层模型, 研究了脉君安片中主要降压活性成分葛根素、钩藤碱与氢氯噻嗪配伍使用前后对氢氯噻嗪体外吸收与转运的影响, 探讨了氢氯噻嗪与葛根素、钩藤碱配伍使用时在吸收阶段的药物相互作用。结果表明, 氢氯噻嗪在Caco-2单层细胞模型中的吸收可能存在由载体介导的主动转运, 葛根素能减少P-糖蛋白 (P-gp), 对氢氯噻嗪的外排, 钩藤碱对氢氯噻嗪的吸收转运无显著影响, 葛根素、钩藤碱与氢氯噻嗪合用能增强氢氯噻嗪的吸收。同时, 实验还发现氢氯噻嗪可能是P-gp的作用底物, 且pH值对氢氯噻嗪的转运有重要影响, 在弱酸性条件下, 氢氯噻嗪的吸收比在中性条件下好。     

Exploration of Intestinal Calcium Precipitation as a Barrier to Absorption at High Calcium Doses

Purpose  To investigate the hypothesis that intestinal bicarbonate secretions precipitate calcium as the carbonate salt, thereby resulting in poor absorption (20–40%) from calcium supplements. Methods  The in vitro effect of calcium dose and bicarbonate secretion rate on soluble calcium was determined by neutralizing elemental Ca²⁺(250, 475, and 630 mg) in 0.1 N HCl to pH 7 with a bicarbonate secretion rate of 0.12 or 1.2 mEq/min. P _CO2 and pH of the solutions were monitored. Soluble calcium was analyzed using atomic absorption spectrometry. Additionally, the transport of calcium across Caco-2 cell monolayers was determined. Results  Calcium from a 250 mg dose remained soluble during bicarbonate secretion, regardless of rate. Once the dose increased, the calcium remaining in solution decreased during neutralization with bicarbonate. The Ca²⁺/CaHCO₃ ⁺ ratio had no effect on calcium permeation across Caco-2 cell monolayers. Conclusions  The physicochemical mechanism of intestinal calcium precipitation supports published clinical data by suggesting that once the solubility product of calcium carbonate is reached, increasing the calcium dose results in significant precipitation at intestinal pH values.     

甘草与甘遂的配伍对大鼠肠黏膜P-gp的影响

评价甘草与甘遂配伍对大鼠肠黏膜P糖蛋白 (P-glycoprotein) 的影响。通过对大鼠口服甘草煎液、甘遂煎液、甘草甘遂合煎液及其合并液1周后, 使用垂直型扩散池 (ussing chamber) 技术, 体外评价罗丹明123 (rhodamine123, R123) 和荧光素钠 (fluorescein sodium, CF) 经大鼠空肠黏膜的经时吸收方向和分泌方向的透过量和表观渗透系数。R123和CF在接受室的浓度用荧光分光光度计检测。应用实时荧光定量聚合酶链式反应技术 (real-time fluorescent quantitative polymerase chain reaction) 检测mdr1a基因在肠黏膜中的表达。在ussing chamber实验中, 4种药液除甘草外均具有增加R123经吸收方向 (mucosa to serosa, M-S) 透过性和减少分泌方向 (serosa to mucosa, S-M) 透过性的趋势。甘草只增加了R123吸收方向的透过, 但对分泌方向影响不大, 且均无统计学意义; 甘遂组与合煎组均使R123 S-M透过明显减少 (P < 0.01); 合并组明显增加了R123 M-S的透过 (P < 0.05)。各组的泵出比均明显降低 (P < 0.05)。而rt-pcr实验中, 评价甘遂对肠黏膜的P-gp活性的影响时, 发现大鼠灌胃7 d和14 d甘遂后, 与对照组相比都有下调mdr1a表达的趋势, 但是没有统计学意义。另外, 在评价甘草与甘遂对旁细胞转运CF影响的实验中, 甘遂组、合煎组和合并组均明显减少了CF S-M的透过 (P < 0.01); 甘遂组、合煎组和合并组则均明显减少了CF M-S的透过 (P < 0.05), 但甘草对CF转运的影响没有统计学意义。甘遂可能是一种P-gp抑制剂, 而甘草与甘遂合用后对R123透过的影响与单用甘遂相似, 可能是甘草与甘遂有协同作用, 使其毒性成分吸收增加, 这可能是两者配伍产生毒性的机制之一。     

Characterization of Substrates and Inhibitors for the In Vitro Assessment of Bcrp Mediated Drug–Drug Interactions

Purpose   In vitro assessment of drug candidates' affinity for multi-drug resistance proteins is of crucial importance for the prediction of in vivo pharmacokinetics and drug–drug interactions. To have well described experimental tools at hand, the objective of the study was to characterize substrates and inhibitors of Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp). Methods  Madin–Darbin canine kidney cells overexpressing mouse Bcrp (MDCKII-Bcrp) were incubated with various Bcrp substrates, or a mixture of substrate and inhibitor to either the apical (A) or basolateral (B) compartment of insert filter plates. Substrate concentrations in both compartments at time points t = 0 h and t = 2 h were determined by LC–MS/MS, and respective permeation coefficients (P _app) and efflux ratios were calculated. Results  The Bcrp inhibitor Ko143 blocked topotecan and ABZSO transport in a concentration-dependent manner. P-gp inhibitors ivermectin, LY335979, PSC833, and the P-gp/Bcrp inhibitor ritonavir did not influence Bcrp mediated topotecan transport, however, blocked ABZSO transport. Additionally, neither was ABZSO transport influenced by topotecan, nor topotecan transport by ABZSO. Conclusions  Data suggest different modes of substrate and inhibitor binding to Bcrp. In order to not overlook potential drug–drug interactions when testing drug candidates for inhibitory potential towards Bcrp, distinct Bcrp probe substrates should be used.     

Saturable Absorptive Transport of the Hydrophilic Organic Cation Ranitidine in Caco-2 Cells: Role of pH-Dependent Organic Cation Uptake System and P-Glycoprotein

Purpose The purpose of this work was to investigate the involvement of carrier-mediated apical (AP) uptake and efflux mechanisms in the absorptive intestinal transport of the hydrophilic cationic drug ranitidine in Caco-2 cells. Methods Absorptive transport and AP uptake of ranitidine were determined in Caco-2 cells as a function of concentration. Permeability of ranitidine in the absorptive and secretory directions was assessed in the absence or presence of the P-glycoprotein (P-gp) inhibitor, GW918. Characterization of the uptake mechanism was performed with respect to inhibitor specificity, pH, energy, membrane potential, and Na⁺ dependence. Efflux from preloaded monolayers was evaluated over a range of concentrations and in the absence or presence of high extracellular ranitidine concentrations. Results Saturable absorptive transport and AP uptake of ranitidine were observed with K_m values of 0.27 and 0.45 mM, respectively. The ranitidine absorptive permeability increased and secretory permeability decreased upon inhibition of P-gp. AP ranitidine uptake was inhibited in a concentration-dependent fashion by a diverse set of organic cations including tetraethylammonium, 1-methyl-4-phenylpyridinium, famotidine, and quinidine. AP ranitidine uptake was pH and membrane potential dependent and reduced under conditions that deplete metabolic energy. Efflux of [³H]ranitidine across the basolateral membrane was neither saturable as a function of concentration nor trans stimulated by unlabeled ranitidine. Conclusions Saturable absorptive transport of ranitidine in Caco-2 cells is partially mediated via a pH-dependent uptake transporter for organic cations and is subject to attenuation by P-gp. Inhibition and driving force studies suggest the uptake carrier exhibits similar properties to cloned human organic cation transporters. The results also imply ranitidine transport is not solely restricted to the paracellular space.     

Characterisation of (<Emphasis Type="Italic">R</Emphasis>/<Emphasis Type="Italic">S</Emphasis>)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein

Digoxin is a drug with a narrow therapeutic index, which is a substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to the inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidney. It is well known that serum concentrations of digoxin increase considerably in humans if propafenone is given simultaneously. However, it has not been investigated in detail whether propafenone and its metabolites are substrates and/or inhibitors of human P-glycoprotein. The aim of this study, therefore, was to investigate the P-glycoprotein-mediated transport and inhibition properties of propafenone and its major metabolites 5-hydroxypropafenone and N-desalkylpropafenone in Caco-2 cell monolayers. Inhibition of P-glycoprotein-mediated transport by propafenone and its metabolites was determined using digoxin as a P-glycoprotein substrate. No polarised transport was observed for propafenone and N-desalkylpropafenone in Caco-2 cell monolayers. However, 5-hydroxypropafenone translocation was significantly greater from basal-to-apical compared with apical-to-basal (P_app basal–apical vs. P_app apical–basal, 10.21±2.63×10^–6 vs. 4.34±1.84×10^–6 cm/s; P<0.01). Moreover, propafenone, 5-hydroxypropafenone and N-desalkylpropafenone inhibited P-glycoprotein-mediated digoxin transport with IC₅₀ values of 6.8, 19.9, and 21.3 M, respectively. In summary, whereas propafenone and N-desalkylpropafenone are not substrates of P-glycoprotein, 5-hydroxypropafenone is translocated by human P-glycoprotein across cell monolayers. In addition, propafenone and its two major metabolites 5-hydroxypropafenone and N-desalkylpropafenone are inhibitors of human P-glycoprotein and therefore contribute to the digoxin–propafenone interaction observed in humans.     

Increased plasma concentrations of an antidyslipidemic drug pemafibrate co-administered with rifampicin or cyclosporine A in cynomolgus monkeys genotyped for the organic anion transporting polypeptide 1B1

In vitro permeability and in vivo pharmacokinetics of pemafibrate were investigated in human intestinal and animal models untreated or pretreated with cyclosporine A or rifampicin to evaluate any drug interactions. Ratios of basal to apical apparent permeability (P_app) over apical to basal P_app in the presence of pH gradients decreased from 0.37 to 0.080 on rifampicin co-incubation, suggesting active transport of pemafibrate from basal to apical sides in intestinal models. Plasma concentrations of intravenously administered pemafibrate were enhanced moderately in control mice but only marginally in humanized-liver mice by oral pretreatment with rifampicin [an organic anion transporting polypeptide (OATP) 1B1 inhibitor] 1 h before the administration of pemafibrate. In three cynomolgus monkeys genotyped as wild-type OATP1B1 (2 homozygous and 1 heterozygous), oral dosing of cyclosporine A 4 h or rifampicin 1 h before pemafibrate administration significantly increased the areas under the plasma concentration–time curves (AUC) of intravenously administered pemafibrate by 4.9- and 7.4-fold, respectively. Plasma AUC values of three pemafibrate metabolites in cynomolgus monkeys were also increased by cyclosporine A or rifampicin. These results suggested that pemafibrate was actively uptaken in livers and rapidly cleared from plasma in cynomolgus monkeys; this rapid clearance was suppressible by OATP1B1 inhibitors.