HPLC法同时测定人血浆中霉酚酸与霉酚酸葡糖苷酸的浓度

目的:建立以高效液相色谱法同时测定人血浆中霉酚酸(MPA)与霉酚酸葡糖苷酸(MPAG)浓度的方法。方法:色谱柱为LunaC18,流动相为(20mmol·L-1磷酸二氢钾+40mmol·L-1四丁基溴化铵(pH5·5))-乙腈=73:27,流速为1·6mL·min-1,MPA与MPAG采用二极管阵列检测器和荧光检测器串联检测,MPAG检测波长为250nm,MPA荧光检测波长为316nm(激发波长)、430nm(发射波长),柱温为38℃,其中血样加乙腈沉淀蛋白后进样10μL。结果:MPA、MPAG检测浓度分别在0·2～20(r=0·9993)、1～100(r=0·9999)μg·mL-1范围内与峰面积积分值呈良好线性关系,最低检测限分别为0·05、0·1μg·mL-1;平均回收率分别为95·54%、100·22%;MPA日内、日间RSD均<6%,MPAG日内、日间RSD均<4%。结论:本方法快捷、简便、灵敏,可用于测定人血浆中MPA与MPAG的浓度。     

Liposome-Mediated Targeting of Enzymes to Cancer Cells for Site-Specific Activation of Prodrugs: Comparison with the Corresponding Antibody-Enzyme Conjugate

Purpose. Immunoenzymosomes are tumor-targeted immunoliposomes bearing enzymes on their surface. These enzymes are capable of converting relatively nontoxic prodrugs into active cytostatic agents. The aims of this study were to compare the enzyme delivery capability of immunoenzymosomes with that of the corresponding antibody-enzyme conjugate and to evaluate whether immunoenzymosomes are able to mount a strong bystander effect. Methods. Immunoenzymosomes exposing Fab fragments of the monoclonal antibody 323/A3 and the bacterial enzyme -glucuronidase or the corresponding antibody-enzyme conjugate were incubated with OVCAR-3 cells (human ovarian carcinoma cells). Cell-associated enzymatic activity and the in vitro antiproliferative effect of a glucuronide prodrug of doxorubicin (DOX-GA3) were determined. Results. At equal numbers of carrier units, the cell-associated enzymatic activity achieved by using immunoenzymosomes was 15-fold higher than that obtained after incubation with the corresponding antibody-enzyme conjugate. Increasing the amount of antibody-enzyme conjugate added to the cells could not compensate for their lower enzyme delivery capability. Immunoenzymosomes were able to induce inhibition of cell growth not only of tumor cells to which immunoenzymosomes were bound but also of a large number of neighboring cells. Conclusions. Immunoenzymosomes are able (a) to target prodrug-converting enzymes more efficiently to tumor cells than the corresponding antibody-enzyme conjugate and (b) to mount a strong bystander effect.     

HPLC法测定人血浆中霉酚酸的浓度及药动学研究

目的:建立以高效液相色谱法测定人血浆中霉酚酸浓度的方法,并对其在人体内的药动学参数进行研究。方法:霉酚酸血浆样品经甲醇沉淀后直接进样测定,其中色谱柱为Symmetry Shield C18,流动相为乙腈-水-三乙胺(40∶60∶0.3),流速为1.0mL·min-1,柱温为30℃,测定波长为218nm,进样量为20μL。结果:霉酚酸检测浓度在0.2~50mg·L-1范围内与峰面积积分值线性关系良好(r=0.9996),定量下限为0.2mg·L-1;平均方法回收率为101.94%,平均提取回收率为87.06%;日内、日间RSD均<6%。另,人体药动学研究表明,霉酚酸在体内存在肠肝循环导致双峰出现,人体过程符合单室开放模型。结论:本方法简便、灵敏、专一、准确、精密,可用于霉酚酸的药动学研究。     

Visible Light Controlled Release of Anticancer Drug through Double Activation of Prodrug

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Pyrazolo[3,4-d]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors

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Phosphoramidate Prodrugs Continue to Deliver,The Journey of Remdesivir (GS-5734) from RSV to SARS-CoV-2

Remdesivir (GS-5734) is a monophenol, 2-ethylbutylalanine phosphoramidate prodrug of a 1′-cyano-4-aza-7,9-dideazaadenosine C-nucleoside (GS-441524) that is FDA approved for the treatment of hospitalized patients with COVID-19. The prodrug, initially invented for respiratory syncytial virus, was later found to have activity toward emerging RNA viruses, including Ebola and coronaviruses. Remdesivir is among the first examples of a phosphoramidate prodrug aimed at delivering a nucleoside monophosphate into lung cells to efficiently generate the nucleoside triphosphate inhibitor of viral RNA polymerases. With remdesivir as the central case study, the present work describes the antiviral potency and in vitro metabolism evidence for lung cell activation of phosphoramidates, together with their in vivo pharmacokinetics, lung distribution, and antiviral efficacy toward respiratory viruses. The lung delivery of nucleoside monophosphate analogs using prodrugs warrants further investigation toward the development of novel respiratory antivirals.     

抗肿瘤前药-姜黄素衍生物的设计合成及初步活性测试

目的:为了提高姜黄素的抗癌活性及选择性,考虑将之做成前药形式.方法:从几种氨基酸出发,经过马来酸酐活化后与姜黄素结合,得到四个化合物.利用MTT法对四个目标化合物进行了体外抗肿瘤活性评价.结果与结论:其结构经IR,1HNMR和13CNMR确证.目标化合物对胰腺癌细胞株SW-1990和膀胱癌细胞株T24的抑制试验结果表明,四个化合物对这两种细胞的抑制作用均优于阳性对照药5-Fu.     

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

l-seryl, and sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into 1, highly active locally at a low dose in a mouse airway hypereosinophilia model.     

Transcorneal Permeation of l- and d-Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement

PURPOSE: The aim of this study was to evaluate the contribution of amino acid transporters in the transcorneal permeation of the aspartate (Asp) ester acyclovir (ACV) prodrug. METHODS: Physicochemical characterization, solubility and stability of acyclovir L: -aspartate (L: -Asp-ACV) and acyclovir D: -aspartate (D: -Asp-ACV) were studied. Transcorneal permeability was evaluated across excised rabbit cornea. RESULTS: Solubility of L: -Asp-ACV and D: -Asp-ACV were about twofold higher than that of ACV. The prodrugs demonstrated greater stability under acidic conditions. Calculated pK(a) and logP values for both prodrugs were identical. Transcorneal permeability of L: -Asp-ACV [Formula: see text] was fourfold higher than D: -Asp-ACV [Formula: see text] and ACV [Formula: see text]. ACV generation during the transport process was minimal. L: -Asp-ACV transport was sodium and energy dependent but was not inhibited by glutamic acid. Addition of BCH, a specific B(0,+) and L amino acid transporter inhibitor, decreased transcorneal L: -Asp-ACV permeability to [Formula: see text]. L: -Asp-ACV and D: -Asp-ACV did not demonstrate significant difference in stability in ocular tissue homogenates. CONCLUSION: The results demonstrate that enhanced transport of L: -Asp-ACV is as a result of corneal transporter involvement (probably amino acid transporter B(0,+)) and not as a result of changes in physicochemical properties due to prodrug derivatization (permeability of D: -Asp-ACV and ACV were not significantly different).     

Antibody‐Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies

The antibody‐directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non‐toxic prodrugs in cancerous tissue by targeted antibody–enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC‐1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., β‐d ‐galactosidase). Furthermore, the drugs show very high cytotoxicities with IC₅₀ values of as low as 4.5 pm . In this report, we summarize our recent results on the development and biological evaluation of these novel third‐generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.     

Amino Acid Ester Prodrugs of Floxuridine: Synthesis and Effects of Structure,Stereochemistry, and Site of Esterification on the Rate of Hydrolysis

Purpose. To synthesize amino acid ester prodrugs of floxuridine (FUdR) and to investigate the effects of structure, stereochemistry, and site of esterification of promoiety on the rates of hydrolysis of these prodrugs in Caco-2 cell homogenates. Methods. Amino acid ester prodrugs of FUdR were synthesized using established procedures. The kinetics of hydrolysis of prodrugs was evaluated in human adenocarcinoma cell line (Caco-2) homogenates and pH 7.4 phosphate buffer. Results. 3-Monoester, 5-monoester, and 3,5-diester prodrugs of FUdR utilizing proline, L-valine, D-valine, L-phenylalanine, and D-phenylalanine as promoieties were synthesized and characterized. In Caco-2 cell homogenates, the L-amino acid ester prodrugs hydrolyzed 10 to 75 times faster than the corresponding D-amino acid ester prodrugs. Pro and Phe ester prodrugs hydrolyzed much faster (3- to 30-fold) than the corresponding Val ester prodrugs. Further, the 5-monoester prodrugs hydrolyzed significantly faster (3-fold) than the 3,5-diester prodrugs. Conclusions. Novel amino acid ester prodrugs of FUdR were successfully synthesized. The results presented here clearly demonstrate that the rate of FUdR prodrug activation in Caco-2 cell homogenates is affected by the structure, stereochemistry, and site of esterification of the promoiety. Finally, the 5-Val and 5-Phe monoesters exhibited desirable characteristics such as good solution stability and relatively fast enzymatic conversion rates.     

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV

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Preparation and Pharmacological Evaluation of Novel Orally Active Ester Prodrugs of Ketoprofen with Non‐Ulcerogenic Property

This study investigates anti‐inflammatory activity with improved pharmacokinetic and non‐ulcerogenic properties of various novel synthesized prodrugs of ketoprofen in experimental animals. Prodrugs 3a , 3f and 3k were found to possess significant anti‐inflammatory activity with almost non‐ulcerogenic potential than standard drug ketoprofen ( 1) in both normal and inflammation‐induced rats. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent drug ketoprofen. These prodrugs are found to have no gastric ulceration with retained anti‐inflammatory activity. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with non‐ulcerogenic potential of ester prodrugs of ketoprofen.     

Vitamin K Prodrugs: 1. Synthesis of Amino Acid Esters of Menahydroquinone-4 and Enzymatic Reconversion to an Active Form

The efficacy and toxicity of vitamin K depends on the pathway and the extent of enzymatic reductive activation to vitamin K hydroquinone, which is an essential cofactor for the synthesis of clotting factors. Parenteral use of vitamin K is impaired by its water insolubility. With the aim to improve delivery problems associated with menahydroquinone-4 (MKH, 2), an active form of menaquinone-4, N,N-dimethylglycine esters of 2 (1-mono, 4-mono, and 1,4-bis) were synthesized and assessed as potential water-soluble prodrugs for parenteral use. The esters can deliver the hydroquinone to its active site without a quinone reductive activation step. The hydrochloride salts of the esters were found to be quite soluble in water. The hydrolysis of the esters in 20% rat liver homogenate 9000 × g supernatant, rat plasma and phosphate buffer, pH 7.4, at 37°C was kinetically studied in the presence and absence of an esterase inhibitor. The hydrolysis was catalyzed by esterases located in the rat liver and rat plasma and quantitatively yielded 2. These results suggest that esterification of 2 with N,N-dimethylglycine is a promising way for obtaining water-soluble prodrug forms of 2. Based on the high susceptibility to liver esterase, the esters are potential prodrugs for achieving the site-specific delivery of 2.     

全反式维甲酸-正丁酸（丙戊酸）前体药物的设计、合成及抗肿瘤活性研究

目的合成全反式维甲酸（ATRA）的前体药物，增强ATRA对急性早幼粒白血病（APL）细胞的分化诱导作用。方法以乙二醇、对苯二酚、乙醇胺及乙二胺等为连接物，通过酯键和酰胺键将分化诱导剂ATRA与组蛋白去乙酰酶（mAC）抑制剂正丁酸、丙戊酸连接起来，形成前体药物。结果合成了13个ATRA与正丁酸或丙戊酸相连接的前体药物，化合物的结构经^1H-NMR、MS和IR确证。结论考察部分化合物对急性早幼粒细胞白血病细胞株NB4的生长抑制作用和对急性早幼粒白血病（APL）细胞分化诱导作用，初步的药理实验结果表明，ATRA与丙戊酸通过酰胺键连接时，对NB4细胞分化诱导能力显著增加。     

Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity

5-Nitro-furan nitrones (1) and 5-nitro-thiophene nitrones (2) were synthesized in one step. Compounds 1a–c had the most potent leishmanicidal activity against intracellular amastigote forms of Leishmania amazonensis and L. infantum (from 0.019 to 2.76 μM), with excellent selectivity (from 39 to 5673). The comparison of the leishmanicidal activity in promastigotes of wild type L. donovani with those overexpressing nitroreductases NRT1 or NRT2 shows that 1a,b are activated by both, which could slow the development of resistance. Their redox potential (E_redox) obtained by cyclic voltammetry (−0.67 and −0.62 V) shows that the reduction of the nitro group is modulated by the nitrone group. Oral administration of 1b to mice infected by L. infantum reduced the parasite load on the spleen by 76.6 and 95.0% with doses of 50 and 100 mg/kg, respectively, administered twice a day, for 5 days. In the liver, the parasite load suppression was above 75% with either treatment.     

灯盏乙素苷元4'-L-氨基酸衍生物的设计、合成与抗氧化活性

为了设计合成具有较强神经细胞氧化损伤保护作用及较好理化性质的灯盏乙素苷元4'-L-氨基酸衍生物,以灯盏乙素苷元为先导化合物,根据主动转运原理在改善口服药物生物利用度应用上取得的成功经验,采用拼合设计原理在先导化合物的4'-羟基上引入L-氨基酸酯、醚结构,设计、合成灯盏乙素苷元4'-L-氨基酸衍生物。采用H2O2诱导PC12细胞氧化损伤模型对设计化合物进行了体外抗氧化活性评价,同时进行了目标化合物理化性质研究。结果发现设计的化合物均具有抗氧化活性,5个化合物抗氧化活性优于VE,灯盏乙素苷元L-氨基酸醚类化合物在缓冲液中稳定性(t1/2 9～92 h)优于酯类衍生物(t1/2 0.5 h),灯盏乙素苷元L-氨基酸酯类衍生物18、19与醚类衍生物22、24～27的水溶解度分别为1 796～4 100μg·mL-1和27.7～81.1μg·mL-1,两者水溶性分别达到灯盏乙素的120～280倍和2～6倍。以上研究提示L-氨基酸前药设计策略可适用于灯盏乙素苷元的结构修饰,以获得具有较好抗氧化活性及理化性质的灯盏乙素苷元前药。     

乏氧响应型纳米药物的设计、合成及其抗肿瘤作用研究

乏氧是实体肿瘤的主要特征之一,不仅在血管生成、肿瘤转移等方面起到了举足轻重的作用,还能促进肿瘤细胞产生耐药性,从而削弱化疗、放疗和光动力疗法等治疗作用。同时,肿瘤乏氧区域表现出来的低氧特征以及高度生物还原性微环境也为设计响应型抗癌纳米药物提供了可能。综述基于肿瘤乏氧而发展起来的化疗前药和治疗策略,重点阐述近年来涌现的一类可响应乏氧进行药物释放/治疗的纳米药物体系,以期为临床抗肿瘤研究提供新的思路。     

Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat,Dog, and Primate

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Rational Design of a Dual-Mode Optical and Chemical Prodrug

Purpose The purpose of this study is to demonstrate the rational design and behaviour of the first dual-mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system.Methods A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution.Results The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30 × 10⁻² s⁻¹, while chemical, hydrolytic liberation proceeded independently at 1.89 × 10⁻³ s⁻¹. The photochemical and hydrolytic reactions were both quantitative.Conclusions This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.