前药原理在药物研究中的应用与进展

前药具有提高生物利用度,增加水溶性,减少不良反应等特性,在保持或增强原药药效的同时又克服了原药的缺点。本文主要综合前药原理在药物研究中的典型实例,介绍前药原理在药物研究中的应用。     

前药原理在抗肿瘤药物研究中的应用

前药具有提高生物利用度、增加水溶性、降低毒副作用等特性,在保持或增强原药药效的同时又克服了原药的缺点。前体药物通过对抗肿瘤原药的化学结构或药物剂型进行一定的修饰,从而克服了化疗药物的缺点,开辟了一条抗肿瘤新药研发的新途径。本文主要综述前药原理在抗肿瘤药物研究中的实例及其研究进展。     

前药原理在非甾体抗炎药中的应用

前药 (ｐｒｏ ｄｒｕｇ)原理系指用化学方法将有活性的原药转变成无活性衍生物 ,在体内经酶促或非酶促反应释放出原药而发挥疗效 ,其目的在于提高药物生物利用度 ,增加药物稳定性 ,减小毒副作用 ,促使药物长效化 ,掩饰不适臭味等。前药的主要类型有载体前药 (ｃａｒｒｉｅｒｐｒｏｄｒｕｇ)、协同前药(ｍｕｔｕａｌｐｒｏｄｒｕｇ)、聚合前药 (ｐｏｌｙｍｅｒｉｃｐｒｏｄｒｕｇ)等。非甾体抗炎药 (ＮＳＡＩＤｓ)是临床上治疗风湿性、类风湿性关节炎和骨关节炎的重要药物 ,其主要作用机制是抑制了致炎前列腺素 (ＰＧｓ)的生物合成 ,从而改善…     

前药设计原理及其临床应用

前药是药物分子的生物可逆的衍生物,在体内经酶或化学作用释放具有活性的原药,从而发挥预期的药理作用。在药物的发现和发展过程中,前药已经成为一种确切的改善原药理化性质、生物药剂学性质及药物代谢动力学性质的手段。目前在世界范围内批准上市的药品中有5％～7％可以归类为前药,并且在新药研究的早期前药这一理念也越来越受到重视。本文对一些经典的可以进行前药设计的官能团进行综述,并且以一些利用前药设计原理成功上市的药物为例来阐述前药策略的可行性与优越性。     

磷酸酯类前药设计及其合成方法研究进展

前药概念由A Albert于1951年首先提出，其定义为：前药是一类体外活性较小或无活性，在体内经酶或非酶作用，释出活性物质而发挥药理作用的化合物。前药的结构通常分为原药和载体两个部分。前药设计是在原药最适宜的功能基上键合载体分子，这个键合过程要求能够简便和高效合成，在体内又能完全逆转以释放原药，而且在体内前药与载体都没有明显的生物活性。     

前药的研究进展

前药设计已成为药物化学发展的一个重要方向。通过化学方法将载体分子与原药连接,不仅能增加药物的吸收,而且还能提高药物在体内的选择性,因此它也可以看成是一种载体前药。前药设计的成功在很大程度上取决于载体分子的正确选择,载体的发展不断地推动着前药的发展。依托载体分子进展的前体药物设计和应用将会使前药在药物化学领域发挥越来越重要的作用。     

前药载体研究新进展

<正>前体药物(Prodrug),是指一种口服后经体内化学或酶代谢,能释放出有药效活性的代谢物或原药的化合物。它将原药与一种载体经化学键连接,形成暂时的化学结合物或覆盖物,从而修饰或改变原药的理化性质,经体内降解发挥其药效。前药已经在药物结构修饰及化学发展中发挥了巨大的作用,将成为21世纪药物设计与开发的重要手段。前药结构通常分为原药和载体两部分,前药设计就是在原药最适宜的功能基上键合载体分子。这个键合过程要求能在实     

三环苦参酯类前药的设计、合成及其药动学研究

目的设计合成全新三环苦参酯类前药衍生物,旨在改善其体内药动学行为。方法以苦参碱为原料,经碱水解开环、羧基成酯、12N-苄基取代、甲酯还原得到三环苦参醇母体化合物。采用两种前药制备策略,合成11个酯类前药和2个含有二硫键的前药化合物。选用SD大鼠测定化合物的口服药动学(PK)参数。结果与结论合成了13个未见文献报道的全新结构的三环苦参酯类前药,其结构经HR-MS、~1H-NMR、~(13)C-NMR谱确证。药动学研究表明,不同类型前药的主要药动学参数均低于原药,cLogP值在合理范围内(0~4)的原药可能不适合使用前药策略来改善其药动学行为。     

前药的药代动力学研究进展

前药是自身无活性,在体内经生物转化后释放出有药效活性的代谢物或原药的化合物。前药设计已成为改善药物的一些不良性质如水溶性低、生物利用度差、半衰期太短及缺乏理想的靶向性等的一种重要手段。然而如何从药物代谢动力学角度评价前药尚缺乏统一的标准。本文对近年来前药的药代动力学研究状况进行了概括总结,并提出如何从吸收、分布、代谢和排泄角度对前药的药代动力学性质进行全面评价。     

水溶性紫杉醇前药的制备及抗肿瘤活性的研究

目的紫杉醇是具有良好抗肿瘤疗效的化学药物,由于紫杉醇本身化学结构复杂,难溶于水,在一定程度上限制了紫杉醇药物在临床上的广泛应用,因此改善紫杉醇水溶性是解决紫杉醇药物不足的关键问题。方法本实验选用水溶性叶酸配体作为"导向基团",谷氨酸为连接叶酸和紫杉醇的Linker,氨基PEG(MW:350)为药物增溶剂和稳定剂,制备水溶性叶酸-PEG-谷氨酸-紫杉醇前药。用LC-MS鉴定前药的化学结构,通过对前药溶解性及释药动力学曲线的测定,确定前药的理化性质。用MTT实验分析并对比紫杉醇原药与前药在不同肿瘤细胞(MCF-7、MDA-MB-231、A549)和正常细胞HELF(人胚肺成纤维细胞)中的毒性和药效作用。用荧光标记法直观观察紫杉醇前药在肿瘤细胞和组织中的靶向性。结果实验结果证明已成功合成叶酸-PEG-谷氨酸-紫杉醇前药,并具有较好的溶解性和原药释放动力学曲线,细胞实验表明在叶酸受体-配体作用的介导下,叶酸-PEG-谷氨酸-紫杉醇前药靶向叶酸受体高表达的肿瘤细胞,减少对叶酸受体低表达正常细胞的毒副作用。结论叶酸-PEG-谷氨酸-紫杉醇前药具有良好的抗肿瘤活性。     

The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

Gemcitabine prodrugs with d- and l-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing d-configuration amino acids were enzymatically more stable than ones with l-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3–17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing d-configuration amino acids in cell homogenates was 2.2–10.9-fold slower than one of amino acid monoester prodrugs with l-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of d-amino acid gemcitabine prodrugs was observed more than one of l-amino acid gemcitabine prodrugs. In general, the 5′-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5′-d-valyl-gemcitabine and 5′-d-phenylalanyl-gemcitabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients.     

Spacer/Linker based synthesis and biological evaluation of mutual prodrugs as antiinflammatory agents

Mutual prodrugs of some antiinflammatory agents were synthesized with the aim of improving the therapeutic index through prevention of gastrointestinal complications and to check the efficiency of release of the parent drug in presence of spacer. These mutual prodrugs were synthesized by direct condensation method using dicyclohexyl carbodiimide as a coupling agent and glycine as a spacer. The title compounds were characterized by spectral techniques and the release of the parent drug from mutual prodrug was studied in two different non-enzymatic buffer solutions at pH 1.2, pH 7.4 and in 80% human plasma. All mutual prodrugs exhibited encouraging hydrolysis profile in 80% human plasma. Biological activity of title compounds was studied by carrageenan-induced paw edema method. From the results obtained, it was concluded that these compounds retain the antiinflammatory action.     

Pharmacokinetics and Anticonvulsant Activity of Three Monoesteric Prodrugs of Valproic Acid

The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.     

Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrgs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti-inflamatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethycarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.     

Ocular prodrugs: Attributes and challenges

Ocular drug delivery is one of the most attention-grabbing and challenging endeavors among the numerous existing drug delivery systems. From a drug delivery point of view, eye is an intricate organ to investigate and explore. In spite of many limitations, advancements have been made with the intention of improving the residence time or permeation of the drug in the ocular region. Poor bioavailability of topically administered drugs is the major issue pertaining to ocular drug delivery. Several efforts have been made towards improving precorneal residence time and corneal penetration, e.g. iontophoresis, prodrugs and ion-pairing, etc. Prodrug approach (chemical approach) has been explored by the formulation scientists to optimize the physicochemical and biochemical properties of drug molecules for improving ocular bioavailability. Formulation of ocular prodrugs is a challenging task as they should exhibit optimum chemical stability as well as enzymatic liability so that they are converted into parent drug after administration at the desired pace. This review will encompass the concept of derivatization and recent academic and industrial advancements in the field of ocular prodrugs. The progression in prodrug designing holds a potential future for ophthalmic drug delivery.     

Recent updates in utilizing prodrugs in drug delivery (2013–2015)

ABSTRACT

Introduction: Utilizing the prodrug approach as a method to overcome various pharmaceutical and pharmacokinetic barriers to drug delivery is significantly accelerating and achieving successes. In contrast to the older traditional prodrugs which suffer from decreased bioavailability and a high profile of side effects, due to activation at undesired sites, the targeted prodrug approach utilizes delivery systems to improve delivery for a wide range of therapeutics including anti-cancer, anti-bacterial and anti-inflammatory drugs.

Areas covered: Recent updates in utilization of prodrugs in drug delivery between 2013 and 2015 are discussed. Targeted prodrugs against cancer, solid tumors, microbial infections, inflammation and other diseases using advanced delivery systems such as theranostic approaches, siRNA, DOX immunoconjugate, C 60-ser carrier vector, biotinylated prodrug, human serum albumin (HSA) carrier and others are presented.

Expert opinion: Recent research efforts have been directed at developing targeted prodrugs to replace the classical prodrugs. The use of this approach has accelerated following the emergence of encouraging results from several studies on targeted prodrugs that have highlighted their higher efficiency and improved safety profiles.

Targeted prodrug delivery is now considered more than a chemical modification method. It is an applicable and promising approach and, in the future, better knowledge and wide application of this approach may be attained which may pave the way for more forward-thinking and creative techniques.     

Water‐soluble prodrugs of cyclosporine A with tailored conversion rates

Abstract: A novel type of water‐soluble prodrugs of cyclosporine A (CsA) is described, featuring a modular system of an enzyme‐cleavable group, a solubilizing moiety and a chemodegradable spacer attached to the hydroxyl function of (4R)‐4‐[(E)‐2‐butenyl]‐4‐,N‐dimethyl‐l ‐threonine (MeBmt)‐1 of CsA. The chemical synthesis of these double prodrugs proceeds in high yield and purity and allows for a systematic study of the influence of the structural parameters upon physicochemical and pharmacological properties. The evaluation of the chemical and enzymatic stability results in differential values of the conversion rates (minutes to several hours) in support of an enzyme‐triggered release of the parent drug as the rate‐limiting step. In vitro studies show that the designed prodrug systems can be regarded as soft prodrugs in being devoid of cyclophiline A (CypA) binding and that complete conversion to the parent drug occurs in whole rat blood, setting the stage for therapeutic use.     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.     

Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK

The release of an active drug from the prodrug generates a pro‐fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro‐fragment of the other drug will eliminate the pro‐fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α‐methylene‐γ‐butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α‐methylene‐γ‐butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne‐tagged secondary amine prodrug of α‐methylene‐γ‐butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB‐CDK SymProDs were ~20‐ to 200‐fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.     

Macromolecular Prodrugs. XV. Colon-Targeted Delivery—Bioavailability of Naproxen from Orally Administered Dextran–Naproxen Ester Prodrugs Varying in Molecular Size in the Pig

The bioavailability of naproxen after oral administration of aqueous solutions of various dextran–naproxen ester prodrugs in pigs was determined. The dextran prodrugs employed ranged in molecular weight from 10,000 to 500,000. As calculated relative to an equivalent oral dose of parent naproxen, the absorption fractions of all the derivatives were close to 100%. Only small interindividual variation of naproxen bioavailability was observed. The naproxen plasma profiles for all the administered prodrugs exhibited a characteristic lag time of naproxen appearance in the blood (2–3 hr). Compared to administration of the prodrugs alone, coadministration of excess of the parent dextran further delayed the absorption of naproxen from the GI tract. The results of the present study demonstrate the potential of dextran prodrugs for colon site-specific delivery of drugs containing a carboxylic acid functional group.