肠道P-糖蛋白和细胞色素P4503A对口服药物吸收的联合作用

药物在肠道的Ⅰ相代谢和主动转运是决定口服药物生物利用度的关键因素。细胞色素P450 (CYP) 3A和P-糖蛋白在胃肠道的吸收细胞中高表达，肠道P-糖蛋白和(或)CYP 3A的抑制剂可以增加口服药物的生物利用度。本文综述了肠道P-糖蛋白和CYP 3A对口服药物吸收的联合作用、可能的机制及其在药学中的应用。     

P-糖蛋白在药物代谢动力学中的作用及其临床意义

1970年Biedler与Riehm在小鼠白血病细胞P388及中国仓鼠肺细胞中首先发现多药耐药(multidrugresistance,MDR)现象。1976年Juliano与Ling发现在耐药的中国仓鼠卵巢细胞表面上能表达一种磷糖蛋白(phosphoglycoprotein)即P糖蛋白(P glycoprotein,P gp)[1]。随后的研究不仅发现P gp与MDR的关系,而且发现P gp是由ATP水解而始动的能量依赖的泵出转运子(energy dependent effluxtransporter)。人有2种P gp基因家族(MDR1及MDR3),小鼠有3种P gp基因家族(mdr1a,mdr1b及mdr2)[2]。由人MDR1基因及小鼠mdr1a/1b基因编码的P gp作为药物泵出转…     

P-糖蛋白对布格呋喃大鼠肠道吸收的影响

本研究采用Caco-2细胞摄取和转运模型、大鼠小肠在体循环灌注、大鼠离体小肠翻转肠小囊模型及P-糖蛋白抑制剂维拉帕米(verapamil)和环孢素(cyclosporine A，CsA)研究P-糖蛋白(P-glycoprotein，P-gp)对布格呋喃(buagafuran)自肠道吸收的影响，UV-HPLC方法测定布格呋喃含量。实验结果表明，布格呋喃可被Caco-2细胞转运和摄取，维拉帕米和环孢素可使布格呋喃由Caco-2细胞绒毛面(apical，A)向基底面(basolateral，B)的转运较对照组增加1.4和1.35倍，基底面向绒毛面的转运则减少为对照组的71%和75%。维拉帕米和环孢素可使低浓度布格呋喃摄取量分别增加4.4和3.4倍。布格呋喃自大鼠小肠吸收较快，灌流90 min后残留量仅为10%。维拉帕米和环孢素可加快布格呋喃吸收，以灌流后30 min最为明显(分别提高12.4%和21.5%)。在大鼠小肠翻转肠小囊内液中布格呋喃浓度可在10 min内下降86%。维拉帕米和环孢素均可使小囊液和小囊匀浆中布格呋喃含量明显升高。以上结果提示，布格呋喃是P-糖蛋白的底物，P-糖蛋白可阻碍布格呋喃在小肠的吸收。肠道P-糖蛋白的外排作用可能是导致布格呋喃生物利用度低的重要原因之一。     

P-糖蛋白介导的药代动力学及其药物相互作用

P-糖蛋白是一个能量依赖性转运蛋白,能将许多结构不同的化合物逆向转运出细胞。它除了在肿瘤组织过度表达引起多药耐药外,在人体正常组织肝、肾、小肠、血脑屏障、肌肉组织、肾上腺等部位也有分布,对许多种药物的药代动力学具有调控作用。本文综述P-糖蛋白对药代动力学的作用及由P-糖蛋白的诱导和抑制所引起的药物相互作用。     

由P-糖蛋白介导的药物相互作用研究进展

目的:介绍由P-糖蛋白介导的药物相互作用研究进展。方法:以近几年国内、外有代表性的论文为依据,就P-糖蛋白性质、功能和作用机制在药物相互作用中的运用进行分析和评述。结果:发现P-糖蛋白可以介导抗肿瘤药、循环系统用药、抗生素类药、免疫调节剂、中枢神经系统用药等药物的相互作用。结论:由P-糖蛋白介导的药物相互作用研究不够深入,缺乏系统性研究。     

肠道P-糖蛋白辅料抑制剂的研究进展

位于小肠上皮细胞顶端的P-糖蛋白(P-gp)是一种能量依赖性外排泵，可降低多种底物药物的生物利用度。抑制肠道P-gp以增加药物生物利用度受到越来越多的关注。本文将肠道P-gp辅料抑制剂分为非离子型表面活性剂、聚乙二醇类、 β-环糊精衍生物和壳聚糖硫醇盐，并对其作用机制进行综述。与传统P-gp抑制剂相比，辅料抑制剂的非特异性药理作用极小，因此几乎不产生副作用。辅料抑制剂有望代替传统P-gp抑制剂，广泛用于增加难溶性及低口服吸收药物的肠道吸收，从而增加该类药物的生物利用度。这些辅料抑制P-gp的机制及其临床应用还需更多研究和探讨。     

P-糖蛋白介导的中枢神经系统药物相互作用

P-糖蛋白(P—gp)属于ATP结合盒转运体超家族成员之一,是目前研究较多的一类转运体,它广泛分布于人体的肠、肝、肾、等部位的管腔上皮细胞和脑毛细血管内皮细胞上。由于临床使用的大多数药物都是P—gp底物和或调节剂,容易引起相应的药物相互作用。本文重点介绍了P—gp与血脑屏障、P—gp对中枢神经系统(CNS)药物作用的研究进展、P—gp介导的相互作用及在中枢神经系统上产生的药物效应或副作用。     

CYP3A4和P糖蛋白与药物的肠道处置

肠CYP3A4介导的生物转化和P糖蛋白介导的药物主动泵出肠细胞是决定口服药物生物利用度的主要因素。有证据显示CYP3A4和P糖蛋白在小肠不是共同调节的,但两者在药物肠道处置中的协同作用已得到体外试验和动物体内试验的证实。进一步了解两者的相互作用有助于改善CYP3A4/P糖蛋白底物的生物利用度。     

P-糖蛋白与CYP450酶对千金子肠道毒性的影响

P-糖蛋白和细胞色素CYP450酶为体内重要的转运蛋白和代谢酶,参与药物在体内的吸收和代谢。千金子对胃肠道有强烈的刺激作用,可以产生峻泻,本文将从P-糖蛋白和CYP450酶功能着手分析二者对千金子肠道毒性的影响,为千金子肠道毒性的研究提供新的思路和方法。     

药物制剂技术在抑制P-糖蛋白外排作用中的应用研究近况

P-糖蛋白（P-gp）是一个ATP依赖性药物外排泵,可影响药物代谢动力学,是导致药物吸收差以及肿瘤多药耐药性产生的重要因素。综述P-gp抑制剂的作用机制和具有P-gp抑制作用的药用辅料的实验研究,探讨利用药物制剂技术抑制P-gP对药物的外排作用,促进药物体内吸收,逆转肿瘤多药耐药性。     

肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由MDR1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有明显的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高     

西替利嗪肠吸收机制研究

目的:考察西替利嗪在小肠的吸收特征.方法:采用离体肠外翻法,以HPLC法测定不同浓度西替利嗪在大鼠各肠段的吸收量,并分别计算吸收速率常数(Ka)和表观渗透系数.考察P-糖蛋白(P-gp)抑制剂地高辛和多药耐药相关蛋白-2(Mrp-2)抑制剂丙磺舒对西替利嗪肠吸收的影响.结果:西替利嗪在各肠段均有较好的吸收,Ka和表观渗透系数按空肠、十二指肠、结肠和回肠依次下降.各肠段累积吸收量与浓度呈非线性关系,高浓度时吸收加快.P-gp抑制剂地高辛使西替利嗪的吸收明显增加,而Mrp-2抑制剂丙磺舒对西替利嗪的肠吸收没有明显影响.结论:西替利嗪的转运受P-gp介导,临床应用中需注意P-gp及其底物对西替利嗪体内过程的影响.     

肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由Mdr1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有显著的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高     

Rhubarb decreased the systemic exposure of cyclosporine,a probe substrate of P-glycoprotein and CYP 3A

1.?Rhubarb, rhizome of Rheum palmatum L. (RP), is an important herb in clinical Chinese medicine.

2.?Cyclosporine (CSP) is an immunosuppressant with narrow therapeutic window. The oral bioavailability of CSP was associated with P-glycoprotein (P-gp) and CYP 3A4. CSP was used as a probe substrate to investigate the in vivo modulation effects of RP on P-gp and CYP 3A.

3.?Rats were orally administered 2.5?mg/kg of CSP with and without 0.25 and 1.0?g/kg of RP. The blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay.

4.?Both dosages of RP significantly decreased the C_max and AUC_0–t of CSP in rats. Mechanism studies indicated that RP activated the functions of P-gp and CYP 3A.

5.?RP ingestion reduced the systemic exposure of CSP through activating P-gp and CYP 3A.     

Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein

Rationale The multidrug resistance transporter, P-glycoprotein (P-gp), is involved in efflux transport of several antipsychotics in the blood–brain barrier (BBB).Objectives In the present study, we evaluated the inhibitory effect of the antipsychotics, i.e., risperidone, olanzapine, quetiapine, clozapine, haloperidol, chlorpromazine, a major metabolite of risperidone, 9-OH-risperidone, and a positive control inhibitor, PSC833, on the cellular uptake of a prototypic substrate of P-gp, rhodamine (Rhd) 123, in LLC-PK1 and L-MDR1 cells.Materials and methods After incubation of the antipsychotics (1–100 μM) and the positive (10 μM PSC833) or negative (1% dimethyl sulfoxide) controls with 5 μM Rhd 123 for 1 h, the effects of the antipsychotics on the intracellular accumulation of Rhd 123 were examined using a flow cytometric method.Results All the antipsychotics showed various degrees of inhibitory effects on P-gp activity. The rank order of the concentration of inhibitor to cause 50% of the maximal increment of intracellular Rhd 123 fluorescence (EC₅₀) was: PSC833 (0.5 μM) < olanzapine (3.9 μM) < chlorpromazine (5.8 μM) < risperidone (6.6 μM) < haloperidol (9.1 μM) < quetiapine (9.8 μM) < 9-OH-risperidone (12.5 μM) < clozapine (30 μM). Considering that the antipsychotics’ plasma concentrations are generally lower than 1 μM, the present results suggest that olanzapine and risperidone are the only agents that may inhibit P-gp activity in the BBB. However, most of the antipsychotics are extensively accumulated in tissues. In addition, when given orally, the drug concentrations in the gastrointestinal tract are likely to be high.Conclusions Pharmacokinetic interactions due to inhibition of P-gp activity by the antipsychotics appear possible and warrant further investigation.     

Effects of Intestinal CYP3A4 and P-Glycoprotein on Oral Drug Absorption—Theoretical Approach

Purpose. To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. Methods. A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp-mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. Results. The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. Conclusions. The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc.     

Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein

1. To develop a method to predict the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 or P-glycoprotein, data from clinical drug–drug interaction studies of CYP3A4 and/or P-glycoprotein substrates were analysed. The ratio of inhibitor dose (Dose_i) to inhibition constant (K_i), termed the drug-interaction number, was used to index intestinal drug–drug interaction.

2. From the analysis, it was found that (1) CYP3A4 inhibitors with a drug-interaction number below 2.8?L have a low risk of interacting with substrates which exhibit intestinal first-pass metabolism and those with a drug-interaction number above 9.4?L have a high risk; (2) P-glycoprotein inhibitors with a drug-interaction number below 10.8?L have a low risk of interacting with P-glycoprotein substrates and those with a drug-interaction number above 27.9?L have a high risk; and (3) the drug-interaction number indexes, 2.8?L and 9.4?L for CYP3A4 and 10.8?L and 27.9?L for P-glycoprotein were validated by data from dual CYP3A4/P-glycoprotein substrates.

3. In conclusion, the drug-interaction number is useful for classifying the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. This drug-interaction number-based approach is similar to the method that the US Food and Drug Administration (USFDA) recently proposed in the draft guidance for predicting P-glycoprotein-mediated drug–drug interaction.

     

Mechanistic Study of the Cellular Interplay of Transport and Metabolism Using the Synthetic Modeling Method

Purpose The aims of this study were 1) to demonstrate a new modeling strategy that uses experimental computational models built by the synthetic method and 2) to study the consequences of spatial alignment, or lack thereof, of P-glycoprotein (Pgp) and CYP3A4 on the transport and metabolism of drug-like compounds and the influence of competitive inhibition by metabolites on the transport and metabolism of those compounds. Methods The synthetic method of modeling and simulation was used to construct discrete-event, discrete-space models. Within a framework designed for experimentation, object-oriented software components were assembled into devices representing the efflux transport and metabolism mechanisms within cell monolayers in Caco-2 transwell systems. Results Conditions for transport and metabolism synergism (and lack thereof) were identified. Simulations showed how spatial alignment altered the coordinated influences of Pgp and CYP3A4 on absorption of a series of drug-like compounds. Within those experiments, when the metabolites were also substrates of Pgp, the metabolite levels produced were insufficient to give evidence of a competitive inhibitory effect on either transport or metabolism. Conclusions The results provide evidence of the potential value of using this class of models to improve our understanding of how complex cellular processes influence the transport and absorption of compounds, and the consequences of interventions.