文献翻译带练01 总论
大家好，我是给爷嫁给那美女，欢迎来到我的药代动复试课堂。
药代动复试英语的考核项目与内容，无论线上还是线下都保持一致，所以复试英语的准备方法比较固定。
首先对于考核项目与内容，复试英语要么考英语口语问答，要么考文献翻译，每年只考察其中一种项目。从18年开始统计，19年考英语口语对话，内容涵盖毕业设计，实验设计，药代动名词解释，未来规划等。18年线下，20、21年线上均考察文献翻译，内容涵盖药理、药代动、生物化学，比如20年考过生物利用度相关的文献摘要片段，糖尿病主题的文献片段、氨基酸与蛋白质相关的文献片段等，文献翻译考题约为200词。
然后对于考核形式，就英语口语问答而言，线上线下基本一致，都是老师英文提问，考生英文回答。而文献翻译线上线下都是随机抽一题，先读一遍，然后口头翻译作答。只不过线上抽的是文档，线下抽的是卡片而已。
最后对于准备方法，学长建议在复习专业课与实验的时候，一定要顺道把药理，药代动的专业英语词汇记一记，否则直接在专业词汇上卡壳，就没法翻译和口语回答了。能够识别专业词汇，这就说明了你复习的过程的确是认真看过书的，在考官老师那里的印象也会好很多。再者，需要集中训练文献翻译和英语回答。我的文献翻译带练篇后面的视频会基于药理、药代动、生化相关主题，以例题加答案的形式进行更新，欢迎大家持续关注。英语回答建议大家把中文面试高频题(含自我介绍)
同时准备一份英文版本的面试高频题，并且找研友互相提问训练。我的药代动复试电子版资料里面有《中英文面试高频题》，共26页。题干来源于网络，但参考答案是自己整理编写的，可供参考。最后提醒一下，虽然已经连续两年考文献翻译了，但谁也不能实锤今年也一定考文献翻译，谁也不知道今年会不会考英语口语问答呢？所以还是那句话，文献翻译和英语口语问答两手准备才是万全之策。
文献翻译带练02 bioavailability & intestinal first pass effect
Orally administered drugs are generally absorbed by the small intestine and transported either to the lymphatic system or to the hepatic portal system. In general, lipid soluble drugs and vitamins are transported by the small intestine to the lymphatics, and water-soluble drugs are transported to the hepatic portal system. By avoiding the early hepatic first pass effect, the lymphatic transport system may increase drug bioavailability. In addition to its transport systems, the small intestine may affect drug bioavailability through drug uptake, intestinal first pass effect, recruitment of drugs by chylomicrons, formation and secretion of chylomicrons, and enterohepatic circulation.
参考答案：口服药物通常被小肠吸收并运输到淋巴系统或肝门静脉系统。一般情况下，脂溶性药物和维生素通过小肠输送到淋巴管，水溶性药物输送到肝门静脉系统。通过避免早期肝脏首过效应，淋巴转运系统可增加药物的生物利用度。小肠除转运系统外，还可能通过药物摄取、肠道首过效应、乳糜微粒招募药物、乳糜微粒形成和分泌以及肠肝循环等途径影响药物的生物利用度。
Oral administration of drugs is considered the most convenient route for drug administration that leads to better therapy compliance. drugs must have specified physicochemical properties to be successful candidates for oral administration. The intestinal absorption process is a combination of several events that are governed byvarious factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes . The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. The fraction of the administered dose reaching the blood circulation is called bioavailability (F).
参考答案：口服给药是提高治疗依从性的最方便的给药途径。药物必须具有特定的物理化学性质才能成功用于口服。肠道吸收是由多因素控制的多个过程的组合。多种转运机制通过主动和/或被动过程参与肠上皮细胞的药物吸收。运输的分子随后进行肠道代谢，与肠道运输一起可能影响药物的整体利用度。给药剂量到达血液循环的部分称为生物利用度(F)。
文献翻译带练03 P-GP & Multidrug resistance (MDR)
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors.
参考答案：多药耐药仍然是癌症化疗有效的主要障碍之一。跨膜型ATP结合盒式转运体超家族使多种化疗药物外排的增加是癌症多药耐药的主要原因之一，其中P‐糖蛋白(P‐gp/ABCB1)的作用已被证实。临床上，P‐gp药物外排抑制剂与P‐gp转运底物抗癌药物联合使用，是通过阻断P‐gp介导的多药外排来克服抗癌治疗多药耐药的一种治疗方式。为了筛选无毒、选择性和有效的P-gp外排抑制剂，人们进行了广泛的尝试。
P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small molecule inhibitors affect P-glycoprotein (P-gp) transport function in MDR tumor cells. However, inhibition of P-gp transport function adversely accumulates chemotherapeutic drugs in non-target normal tissues. Moreover, most small-molecule P-gp inhibitors failed in the clinical trials due to the low therapeutic window at the maximum tolerated dose. Therefore, downregulation of ABCB1-gene expression (P-gp) in tumor tissues seems to be a novel approach rather than inhibiting its transport function for the reversal of multidrug resistance (MDR).
参考答案：P-糖蛋白由ATP结合盒式转运体B1基因(ABCB1)编码，在癌症化疗过程中产生多药耐药。几种合成的小分子抑制剂影响多药耐药的肿瘤细胞p -糖蛋白(P-gp)的转运功能。然而，P-gp转运功能的抑制会使化疗药物在非靶向的正常组织中急剧积累。此外，大多数小分子P-gp抑制剂在临床试验中失败，原因是最大耐受剂量的治疗窗较低。因此，下调肿瘤组织中ABCB1基因(P-gp)的表达，而不是抑制其转运功能，可能是逆转多药耐药(MDR)的一种新途径。
文献翻译带练04 P-GP & drug-drug interactions(DDIs)
P-glycoprotein (P-GP) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical drug–drug interactions studies; P-GP and cytochrome P450 (CYP450) enzymes are co-regulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-GP induction is generally less than that of CYP3A. Most P-GP inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-GP at the apical membrane of the kidney proximal tubules.
参考答案：P-糖蛋白是一种外排转运体，影响各种化合物的药代动力学(PK)。体外评估转运体诱导具有挑战性，并不总是能预测体内效应，因此有必要考虑临床药物相互作用研究；孕烷X受体(PXR)和组成型雄烷受体(CAR)共同调节P-糖蛋白和细胞色素P450酶。P-糖蛋白诱导降低底物药物暴露的幅度一般小于CYP3A。尽管已知P-糖蛋白在肾近端小管顶膜上表达，大多数P-糖蛋白诱导剂降低了总生物利用度，但对肾清除率的影响较小。
Recent US Food and drug Administration(FDA)draft guidance on pharmacokinetic drug-drug interactions(DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-GP), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin and fexofenadine are P-GP substrate drugs and has defined P-GP inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-GP are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs.
参考答案：最近，美国食品和药物管理局的药动学的药物相互作用指南草案强调了ABC转运蛋白B1(ATP结合盒式转运蛋白B1或P-糖蛋白）、肝脏有机阴离子转运多肽转运体和乳腺癌抵抗蛋白的临床重要性，因为它们具有广泛的底物特异性和参与药物相互作用的潜力。该指南表明，地高辛和非索非那定是P-糖蛋白的底物药物，并将P-糖蛋白抑制剂定义为在临床药物相互作用研究中使地高辛的AUC(血药浓度-时间曲线下面积)增加至少1.25倍的药物。然而，当细胞色素酶和P-糖蛋白的底物药物同时参与药物相互作用时，在评估细胞色素酶和/或药物转运体对药物相互作用的贡献大小时，药物相互作用机制仍然相当模糊。
文献翻译带练05 Plasma protein binding(PPB)
Major drug-binding components in plasma are albumin (human serum albumin—HSA) , α-acid glycoprotein (AAG), lipoproteins (γ-globulin), and erythrocytes of which drug binding to albumin and AAG has been well studied and extensively published over the past several decades.Although HSA has eight binding sites, capable of binding to endogenous compounds as well as xenobiotics with varying affinities, two major sites of HSA are primarily involved in binding ligands and show a bias toward binding acidic drugs.AAG is an acute-phase protein, synthesized in the liver, shows preference to bind basic and neutral drugs, and whose levels could significantly change in disease/inflammation states. In certain disease states, although levels of AAG remained unchanged, yet its binding capacity was reduced.
参考答案：血浆中主要的药物结合成分是白蛋白(人血清白蛋白- hsa)、α-酸性糖蛋白(AAG)、脂蛋白(γ-球蛋白)和红细胞，在过去的几十年里，白蛋白和α-酸性糖蛋白与药物结合的研究已经广泛发表。虽然白蛋白有八个结合位点，能够结合内源性化合物和不同亲和力的外源性药物，但白蛋白的两个主要位点主要参与结合配体，并倾向于结合酸性药物。α-酸性糖蛋白是一种急性期蛋白，在肝脏中合成。
A majority of drugs bind to certain sites on proteins in plasma at various extents to form drug–protein complex. only the unbound drug is able to distribute to the target site to elicit desired pharmacological effects, undesired adverse outcomes, and to be metabolized and eliminated.the unbound drug concentration in the plasma at steady state (Cup,ss) is considered a reasonable surrogate for the free concentration at target sites. It is known that DDIs associated with altered plasma protein binding because of displacement (dPB) can occur both in vitro and in vivo,with possible impacts on drug PK (unbound and/or total parameters) and intended pharmacodynamics (driven by changes in unbound drug concentrations).
参考答案：大多数药物不同程度地与血浆蛋白的某些位点结合，形成药物-蛋白复合物。只有非结合药物才能分布到靶部位，引起预期的药理作用，不良结果，并被代谢和消除。稳定状态下血浆中游离型药物浓度(Cup,ss)被认为是靶部位游离药物浓度的合理替代。已知，由于置换(dPB)与血浆蛋白结合改变相关的药物相互作用可在体外和体内发生，可能对药物药动学(非结合和/或总参数)和预期药效学(由游离药物浓度的变化驱动)产生影响。
文献翻译带练06 Biopharmaceutics Classification System (BCS)
The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. It is because BCS is based on a scientific framework describing the three rate limiting steps in oral absorption. The three necessary steps for a drug to be absorbed are release of drug from dosage forms,maintenance of dissolved state throughout gastrointestinal(GI) track, and permeation of drug molecules through GI membrane into hepatic circulation. There is a fourth step, enterohepatic metabolism that influences the systemic availability as well as release of metabolites into the systemic circulation.
参考答案：生物药剂学分类系统(BCS)不仅是获得体内生物等效性研究豁免的有用工具，也是新药发现和早期开发的决策工具。这是因为BCS是基于一个描述口服吸收的三个限速步骤的科学框架。药物被吸收的三个必要步骤是药物从剂型释放，在胃肠道(GI)轨道中保持溶解状态，药物分子通过胃肠道膜渗透到肝循环。第四步，肠肝代谢，影响整体生物利用度以及进入体循环的代谢产物的释放。
In December 2017, the U.S. Food and drug Administration (FDA) issued the Guidance for Industry; Waiver of In Vivo Bioavailability and Bioequivalence (BE) Studies for Immediate release Solid Oral Dosage Forms Based on a Biopharmaceutical Classification System(BCS). According to this guidance, to qualify for a BCS‐based biowaiver, the following criteria should be demonstrated for BCS Class III drug products: a. The drug substance is highly soluble b. The drug products (test and reference) are very rapidly dissolving (>85% in 15 min across a physiological pH range) c. The test (T) product and reference listed drug (RLD) formulations are qualitatively the same and quantitatively very similar.
参考答案：2017年12月，美国食品药物管理局(FDA)发布了行业指南;放弃基于生物制药分类系统(BCS)的常释固体口服剂型的体内生物利用度和生物等效性研究。根据本指南，BCS III类药品应证明符合以下标准，才有资格获得基于BCS的生物豁免:a.原料药极易溶解；b.药品(受试品和参比品)溶解速度非常快(在生理pH范围内，15分钟内溶解超过85%)；c.受试品和参比品的配方组成是质量相同，数量相似的。
文献翻译带练07 Cytochrome P450 (CYP) enzymes
Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of drugs, xenobiotics, and endogenous substances. This enzymatic activity can be modulated by intrinsic and extrinsic factors, modifying the organism’s response to medications. Among the factors that are responsible for enzyme inhibition or induction is the release of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ), from macrophages, lymphocytes, and neutrophils. These cells are also present in the tumor microenvironment, participating in the development of cancer.Therefore, the inhibition or induction of CYP enzymes by proinflammatory cytokines in the tumor microenvironment can promote carcinogenesis and affect chemotherapy, resulting in adverse effects, toxicity, or therapeutic failure.
参考答案：细胞色素P450 (CYP)酶负责药物、外源性物质和内源性物质的生物转化(生物转化=代谢)。这类酶的活性可以被内在和外在因素调节，改变机体对药物的反应。从巨噬细胞，淋巴细胞和中性粒细胞中释放的促炎细胞因子，如白介素-1， 白介素-6，肿瘤坏死因子α 和干扰素-γ，是一种影响细胞色素P450 酶抑制或诱导的因素。癌症是一种以有利于细胞存活和增殖的细胞突变为特征的疾病，上述这些细胞也存在于肿瘤微环境中，参与了癌症的发展。因此，肿瘤微环境中促炎细胞因子对CYP酶的抑制或诱导可促进癌变并影响化疗，导致不良反应、毒性或治疗失败。
Cytochrome P450 (CYP) enzymes inhibition, a principal mechanism for metabolism-based drug–drug interactions, usually involves competition with another drug for the same enzyme binding site. For example, desipramine metabolized by CYP2D6 is strongly inhibited by binding of fluoxetine to the same isoenzyme. Enzyme inhibition impairs the biotransformation or clearance of all clinically used drugs including several anticancer agents resulting in higher plasma levels of drugs that influence therapeutic outcome and increase the chances of ADRs. If the drug is a prodrug, then the effect is decreased. Thus, inhibition of CYPs may lead to the toxicity or lack of efficacy of a drug.
参考答案：细胞色素P450 (CYP)酶抑制是基于代谢的药物-药物相互作用的主要机制，通常涉及一种药与另一种药物竞争相同的酶结合位点。例如，去甲丙咪嗪由CYP2D6代谢，它的代谢可受到与同一同工酶结合的氟西汀的强烈抑制。酶抑制损害包括几种抗癌药物在内的所有临床使用药物的生物转化或清除，导致血浆药物水平升高，影响治疗结果并增加不良反应的机会。如果药物是前药，那么药效就会降低。因此，抑制CYPs可能会导致药物的毒性或疗效降低。
文献翻译带练08 bile acids metabolism & Inflammatory bowel disease (IBD)
The synthesis of bile acids comprises the major part of cholesterol metabolism. The insoluble cholesterol is converted to the water-soluble molecules-bile acids, which facilitate the dietary lipids and essential nutrients absorption in intestine in turn. In humans, the majority of cholesterol is hydroxylated by the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1), which is a microsomal oxidase and a member of the P450 enzyme family in liver.The intermediates are then converted to cholic acid (CA) by microsomal sterol 12α-hydroxylase (CYP8B1) and mitochondrial sterol 27-hydroxylase (CYP27A1). In the absence of CYP8B1, the intermediates are converted to chenodeoxycholic acid (CDCA).
参考答案：胆汁酸的合成是胆固醇代谢的主要部分。不溶性胆固醇被转化为水溶性分子即胆汁酸，胆汁酸反过来促进膳食脂质和必需营养物质在肠道中的吸收。在人类中，大多数胆固醇被限速酶—胆固醇7α-羟化酶(CYP7A1)羟基化，它是一种微粒体氧化酶，是肝脏中P450酶家族的成员。中间产物经微粒体固醇12α-羟化酶(CYP8B1)和线粒体固醇27-羟化酶(CYP27A1)转化为胆酸(CA)。在CYP8B1缺失的情况下，中间体转化为鹅去氧胆酸(CDCA)。
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Thus, the concentration of primary and conjugated bile acids is elevated in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity.Thus, the bile acid-gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.
参考答案：炎症性肠病是一种慢性、复发性胃肠道炎症性疾病，发病率日益增高，其发病机制尚不清楚。越来越多的证据表明，肠道微生物群和胆汁酸在肠道稳态和炎症中发挥着关键作用。因此，原发性胆汁酸和共轭胆汁酸的浓度在IBD中升高。反过来，胆汁酸可以调节微生物群落，肠道菌群失调和胆汁酸紊乱损害肠道屏障和免疫功能。因此，胆汁酸-肠道菌群轴与IBD发病密切相关。该轴的调节可能是治疗炎症性肠病的一种新选择。
本期内容就是这样，我是给爷嫁给那美女，欢迎持续关注，再见。