核苷类抗HIV系列前药的化学稳定性及药物动力学研究
|
摘要
艾滋病是严重危害人类健康的全球性传染病。目前，医学界至今仍未成功研究出可以彻底治疗AIDS的方法。核苷逆转录酶抑制剂(NRTIs)一直是主导的抗AIDS药物，研究发展迅速。但NRTIs类药物的临床应用和药代动力学都有一定的缺陷，如d4T、AZT有临床毒性，在血浆中半衰期短(1小时)，代谢差，易产生耐药性等。磷酸酯核苷类前药是近年核苷类药物结构修饰的一个重要方向。尽管在前药设计和合成方面有了很大的成功，但是验证前药机理的核苷释放问题仍然很少有过系统的研究。因此，本论文针对体外活性测试成功的前药，通过药物代谢动力学的研究来考察其能否在体内顺利地实现改善核苷利用的目的。
本论文创新性地结合有机化学基础，分析化学手段，和临床前药物动物体内动力学研究，对具有优秀体外活性的化合物进行系统的筛选和评价，取得了以下的研究结果：
1．对在体外抗病毒实验中显示了很高的抗HIV病毒活性(其抗HIV的IC_(50)值是d4T的1000倍)的化合物，d4T-D-E，采用HPLC，~(31)PNMR，HPLC／MS，ESI-MS~n等综合手段进行体外化学稳定性研究，和水解代谢产物分析。论文发现d4T-D-E在不含酶的水溶液环境中，弱酸性环境有利于该化合物的化学稳定性，但酸性过大，也会加速它的水解；中性条件下有一定的半衰期(12．5小时)；碱性环境立即分解。在水解时，主要有三种可能的代谢途径。第一种为先水解断裂D，然后水解释放出核苷；第二种为直接水解释放出核苷；第三种，d4T-D-E被氧化，然后先水解断裂D，代谢为核苷d4T；或直接释放出核苷。
2．论文建立了一种快速、灵敏的测定小鼠血浆中d4T，d4T-D-E浓度的液质连用定量方法(HPLC／MS／MS MRM法)。经过灵敏度，检测限，精密度和准确度，特异性，基质效应，稳定性确证，应用于d4T-D-E在小鼠体内动力学初步研究。
3．论文通过对d4T-D-E的小鼠体内药物代谢动力学初步研究发现，灌胃给药d4T-D-E进入体内后，很快即代谢为d4T。这与d4T-D-E结构无法耐受体内的磷酸酯酶有很大关系，容易被磷酸酯酶催化分解为d4T和含磷组分。比较其主要药动学参数，相对于直接给药的d4T，d4T-D-E的消除相t_(1／2)较短，相对口服生物利用度为40．31％，没有显示比未改造的核苷d4T更好的药动学性质。因此，该体外活性显著的药物由于不良的体内药动学结果而缺乏进一步临床开发的潜力。
4．本论文采用一锅法合成了分别带有吸电子和推电子基团的六个AZT-5’-含磷衍生物。
5．本论文建立了一种简单、快速、灵敏定量检测大鼠血浆中AZT-5’-含磷系列衍生物的HPLC-ESI-MS／MS MRM方法。对该方法进行灵敏度，检测限，精密度和准确度，特异性，基质效应，稳定性确证。将此法应用于该系列AZT-5’-含磷衍生物的动力学实验。
6．本论文通过大鼠药物动力学实验，研究不同取代基系列化合物在体内的构效关系规律。发现不同取代基对AZT-5’-含磷衍生物的体内动力学有不同影响，吸电子和推电子基团的强弱是主导因素，或与相应酚的pKa大小有着直接的联系。吸电子基团衍生物在体内血浆中检测不到原药，代谢得到的AZT浓度较高。推电子基团衍生物在体内血浆中有一定的稳定性，能随着原药在体内的动力学运转变化，缓慢释放AZT，因此同时检测到原药和代谢物AZT。Y基供电子效应越强，化合物越稳定，在体内释放的AZT越持久，缓释的效果越好。
7．本论文发现改造后的AZT-5’-含磷衍生物的药动学表现有很大提高，半衰期有不同程度延长(2．0-20．4倍)，表观分布容积明显增大(0．6-20．7倍)，平均驻留时间(MRT)增大3．1-40．5倍。修饰后的AZT-5’-含磷衍生物有缓释AZT的可能，能延长体内滞留时间，改进AZT在体内的药物水平，减少药物副作用。具有开发为临床抗HIV药物的潜能。M5能显著延长体内滞留时间，改进AZT在体内的药物水平，增加医疗效果。M3可能有一定的组织靶向性，并且从体内清除快。M4在血液中药物浓度高，吸收好。
本论文的创新之处在于(1)充分利用了HPLC，~(31)P NMR，HPLC／MS，ESI-MS~n等现代分析技术，用于抗艾滋候选化合物d4T-D-E的体外化学稳定性研究，和水解代谢产物分析，提出了可能的水解途径；(2)运用液质连用定量方法(HPLC／MS／MS MRM法)进行药物代谢动力学研究，对抗艾滋候选化合物作临床潜能的深入筛选；(3)通过大鼠体内的动力学实验，研究化学结构和动力学表现间的联系，发现不同取代基对AZT-5’-含磷衍生物的体内药物动力学有不同影响，并提出可能的机理。
Acquired immunodeficiency syndrome (AIDS), caused by the humanimmunodeficiency virus (HIV), has become a global epidemic. Although themorbidity and mortality of AIDS patients have been reduced and the survival time hasbeen prolonged, the present treatments would not eradicate HIV and cure AIDS.NRTIs/NtRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) havedemonstrated wide-spread utility as antiviral and anti-cancer therapeutics. However,the clinical application of AZT, d4T is limited by their bone marrow toxicity andsuppression, low therapeutic index, low localization in brain, and a short half-life inblood. Thus, in an attempt to reduce or abolish its side-effects, to improve on thetherapeutic potential, research has focused on the discovery of pro-drugs.Administration of the nucleoside 5'-phosphates plays an important role in pro-drugapproaches. Unfortunately, the effects of pronucleotide design on the mechanism ofnucleotide release have only been systematically studied in a few cases.
Therefore, in the present dissertation, the in vivo potency, plasma pharmacokineticshave been determined with an original combination of organic chemistry, analyticalchemistry and preclinical in vivo pharmacokinetics, for the candidate compounds thatdemonstrated great in vitro anti-HIV activity.
In the present dissertation, research on hydrolytic stability and analysis ofhydrolysis metabolites of a highly successful candidate, d4T-D-E, were developed byvirtue of modern analytical approaches, such as HPLC, ~(31)P NMR, HPLC/MS,ESI-MS~n. It was originally found that d4T-D-E kept the chemical structure underweak acidic condition, had a half-life time 12.5 hours in neutral pH 7.23, anddecomposed completely under alkaline or strong acidic condition. Three possiblehydrolysis pathways were as follows: D group was cleaved accompanied by phosphiteelimination giving the nucleoside d4T, or nucleoside d4T was cleaved directlyaccompanied by phosphite elimination, or d4T-D-E was oxidated, then accompaniedby phosphate elimination giving the nucleoside d4T.
A rapid, sensitive HPLC/ESI-MS/MS method using multiple reaction monitoring(MRM) was originally built to determine the plasma concentration of d4T, d4T-D-E.The method was validated and the specificity, linearity, lower limit of quantification(LLOQ), precision, accuracy, recoveries and stability were determined. This validatedmethod was employed to the pharmacokinetic studies of d4T, d4T-D-E.
It was shown that d4T-D-E was cleaved to d4T promptly in plasma after oraladministration to mice, which correlates to the structural friability to endogenousalkaline phosphatase. Compared to d4T, pharmacokinetics of d4T-D-E presented ashorter elimination t_(1/2), a low relative bioavailability 40.31%.The candidatecompound was short of clinical potency due to poor pharmacokinetics in spite ofnotable in vitro activity.
In the present dissertation, six phosphorous-containing derivatives of AZT weresynthesized with one-pot procedure.
A rapid, robust, simple HPLC/ESI-MS/MS method using multiple reactionmonitoring (MRM) was originally built to determine the plasma concentration of the6 pro-drugs of AZT. The method was validated and the specificity, linearity, lowerlimit of quantification (LLOQ), precision, accuracy, recoveries and stability weredetermined. This validated method was employed to the pharmacokinetic studies ofthe 6 pro-drugs.
The overall pharmacokinetics of six derivatives of AZT in rats were originallyperformed, and it was found to associate with structure of the compounds, themagnitude of which varied considerably with the nature of the Y substituent. Inparticular, strongly electron-withdrawing substituents correlate with their completeconversion to AZT in rat plasma.
In the present dissertation, it was originally brought forward that the overallpharmacokinetics of 6 pro-drugs improved greatly compared to AZT. The pro-drugsof AZT proved the tendency of sustained release of AZT, longer residence time invivo and increased plasma concentration of AZT. The 6 pro-drugs exhibited successin vivo potency.
本论文创新性地结合有机化学基础，分析化学手段，和临床前药物动物体内动力学研究，对具有优秀体外活性的化合物进行系统的筛选和评价，取得了以下的研究结果：
1．对在体外抗病毒实验中显示了很高的抗HIV病毒活性(其抗HIV的IC_(50)值是d4T的1000倍)的化合物，d4T-D-E，采用HPLC，~(31)PNMR，HPLC／MS，ESI-MS~n等综合手段进行体外化学稳定性研究，和水解代谢产物分析。论文发现d4T-D-E在不含酶的水溶液环境中，弱酸性环境有利于该化合物的化学稳定性，但酸性过大，也会加速它的水解；中性条件下有一定的半衰期(12．5小时)；碱性环境立即分解。在水解时，主要有三种可能的代谢途径。第一种为先水解断裂D，然后水解释放出核苷；第二种为直接水解释放出核苷；第三种，d4T-D-E被氧化，然后先水解断裂D，代谢为核苷d4T；或直接释放出核苷。
2．论文建立了一种快速、灵敏的测定小鼠血浆中d4T，d4T-D-E浓度的液质连用定量方法(HPLC／MS／MS MRM法)。经过灵敏度，检测限，精密度和准确度，特异性，基质效应，稳定性确证，应用于d4T-D-E在小鼠体内动力学初步研究。
3．论文通过对d4T-D-E的小鼠体内药物代谢动力学初步研究发现，灌胃给药d4T-D-E进入体内后，很快即代谢为d4T。这与d4T-D-E结构无法耐受体内的磷酸酯酶有很大关系，容易被磷酸酯酶催化分解为d4T和含磷组分。比较其主要药动学参数，相对于直接给药的d4T，d4T-D-E的消除相t_(1／2)较短，相对口服生物利用度为40．31％，没有显示比未改造的核苷d4T更好的药动学性质。因此，该体外活性显著的药物由于不良的体内药动学结果而缺乏进一步临床开发的潜力。
4．本论文采用一锅法合成了分别带有吸电子和推电子基团的六个AZT-5’-含磷衍生物。
5．本论文建立了一种简单、快速、灵敏定量检测大鼠血浆中AZT-5’-含磷系列衍生物的HPLC-ESI-MS／MS MRM方法。对该方法进行灵敏度，检测限，精密度和准确度，特异性，基质效应，稳定性确证。将此法应用于该系列AZT-5’-含磷衍生物的动力学实验。
6．本论文通过大鼠药物动力学实验，研究不同取代基系列化合物在体内的构效关系规律。发现不同取代基对AZT-5’-含磷衍生物的体内动力学有不同影响，吸电子和推电子基团的强弱是主导因素，或与相应酚的pKa大小有着直接的联系。吸电子基团衍生物在体内血浆中检测不到原药，代谢得到的AZT浓度较高。推电子基团衍生物在体内血浆中有一定的稳定性，能随着原药在体内的动力学运转变化，缓慢释放AZT，因此同时检测到原药和代谢物AZT。Y基供电子效应越强，化合物越稳定，在体内释放的AZT越持久，缓释的效果越好。
7．本论文发现改造后的AZT-5’-含磷衍生物的药动学表现有很大提高，半衰期有不同程度延长(2．0-20．4倍)，表观分布容积明显增大(0．6-20．7倍)，平均驻留时间(MRT)增大3．1-40．5倍。修饰后的AZT-5’-含磷衍生物有缓释AZT的可能，能延长体内滞留时间，改进AZT在体内的药物水平，减少药物副作用。具有开发为临床抗HIV药物的潜能。M5能显著延长体内滞留时间，改进AZT在体内的药物水平，增加医疗效果。M3可能有一定的组织靶向性，并且从体内清除快。M4在血液中药物浓度高，吸收好。
本论文的创新之处在于(1)充分利用了HPLC，~(31)P NMR，HPLC／MS，ESI-MS~n等现代分析技术，用于抗艾滋候选化合物d4T-D-E的体外化学稳定性研究，和水解代谢产物分析，提出了可能的水解途径；(2)运用液质连用定量方法(HPLC／MS／MS MRM法)进行药物代谢动力学研究，对抗艾滋候选化合物作临床潜能的深入筛选；(3)通过大鼠体内的动力学实验，研究化学结构和动力学表现间的联系，发现不同取代基对AZT-5’-含磷衍生物的体内药物动力学有不同影响，并提出可能的机理。
Acquired immunodeficiency syndrome (AIDS), caused by the humanimmunodeficiency virus (HIV), has become a global epidemic. Although themorbidity and mortality of AIDS patients have been reduced and the survival time hasbeen prolonged, the present treatments would not eradicate HIV and cure AIDS.NRTIs/NtRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) havedemonstrated wide-spread utility as antiviral and anti-cancer therapeutics. However,the clinical application of AZT, d4T is limited by their bone marrow toxicity andsuppression, low therapeutic index, low localization in brain, and a short half-life inblood. Thus, in an attempt to reduce or abolish its side-effects, to improve on thetherapeutic potential, research has focused on the discovery of pro-drugs.Administration of the nucleoside 5'-phosphates plays an important role in pro-drugapproaches. Unfortunately, the effects of pronucleotide design on the mechanism ofnucleotide release have only been systematically studied in a few cases.
Therefore, in the present dissertation, the in vivo potency, plasma pharmacokineticshave been determined with an original combination of organic chemistry, analyticalchemistry and preclinical in vivo pharmacokinetics, for the candidate compounds thatdemonstrated great in vitro anti-HIV activity.
In the present dissertation, research on hydrolytic stability and analysis ofhydrolysis metabolites of a highly successful candidate, d4T-D-E, were developed byvirtue of modern analytical approaches, such as HPLC, ~(31)P NMR, HPLC/MS,ESI-MS~n. It was originally found that d4T-D-E kept the chemical structure underweak acidic condition, had a half-life time 12.5 hours in neutral pH 7.23, anddecomposed completely under alkaline or strong acidic condition. Three possiblehydrolysis pathways were as follows: D group was cleaved accompanied by phosphiteelimination giving the nucleoside d4T, or nucleoside d4T was cleaved directlyaccompanied by phosphite elimination, or d4T-D-E was oxidated, then accompaniedby phosphate elimination giving the nucleoside d4T.
A rapid, sensitive HPLC/ESI-MS/MS method using multiple reaction monitoring(MRM) was originally built to determine the plasma concentration of d4T, d4T-D-E.The method was validated and the specificity, linearity, lower limit of quantification(LLOQ), precision, accuracy, recoveries and stability were determined. This validatedmethod was employed to the pharmacokinetic studies of d4T, d4T-D-E.
It was shown that d4T-D-E was cleaved to d4T promptly in plasma after oraladministration to mice, which correlates to the structural friability to endogenousalkaline phosphatase. Compared to d4T, pharmacokinetics of d4T-D-E presented ashorter elimination t_(1/2), a low relative bioavailability 40.31%.The candidatecompound was short of clinical potency due to poor pharmacokinetics in spite ofnotable in vitro activity.
In the present dissertation, six phosphorous-containing derivatives of AZT weresynthesized with one-pot procedure.
A rapid, robust, simple HPLC/ESI-MS/MS method using multiple reactionmonitoring (MRM) was originally built to determine the plasma concentration of the6 pro-drugs of AZT. The method was validated and the specificity, linearity, lowerlimit of quantification (LLOQ), precision, accuracy, recoveries and stability weredetermined. This validated method was employed to the pharmacokinetic studies ofthe 6 pro-drugs.
The overall pharmacokinetics of six derivatives of AZT in rats were originallyperformed, and it was found to associate with structure of the compounds, themagnitude of which varied considerably with the nature of the Y substituent. Inparticular, strongly electron-withdrawing substituents correlate with their completeconversion to AZT in rat plasma.
In the present dissertation, it was originally brought forward that the overallpharmacokinetics of 6 pro-drugs improved greatly compared to AZT. The pro-drugsof AZT proved the tendency of sustained release of AZT, longer residence time invivo and increased plasma concentration of AZT. The 6 pro-drugs exhibited successin vivo potency.
引文
[1]Sun,X.B.;Xun,K.J.;Zhao,Y.F.One-pot synthesis of hydrogen phosphonate derivatives of d4T and AZT.Chemical Communication.2002,20,2414-2415.
[2]周伟澄.高等药物化学选论[M].北京:化学工业出版社.2006.
[3]刘北斗.全球艾滋病流行现状.国外医学.流行病学.传染病学分册.2003,30,55.
[4]顾明,赵杰东,王彦松,段青.人免疫缺陷综合征治疗药物研究进展.西南国防医药.2005,15,107-110.
[5]Clercq,E.D.New anti-HIV agents and targets.Med.Res.Rev.2002,22.531-565.
[6]Telesnitsky,A.;Goff,S.P.Reverse transcriptase and the generation of retroviral DNA [M].//Coffin,J.M.,Hughes,S.H.,Varmu,H.E.In Retroviruses [M].New York: Cold Spring Harbor Laboratory Press,1997,121-160.
[7]Huang,H.;Choora,R.;Vervine G.L.Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance.Science,1998,282,1669-1675.
[8]Sarafianos,S.G.;Dask,Hughas,S.H.Taking aim at moving target: designing drugs to inhibit drug-resistantHIV-1 reverse transcriptases.Curr.Opin.Struct.Biol,2004,14,716-730.
[9]Nikolenko,G.N.;Frankenberry,K.A.;PALMER,S.RNase H domains obtained from treatment-experienced patients increase resistance to AZT.Antiviral.Ther.2005,10 (Suppl1),89.
[10]Sarafianos,S.G.;Clark,A.D.;Tuske S.Trapping HIV-1 reverse transcriptase before and after translocation on DNA.J.Biol.Chem.2003,278,16280-16288.
[11]Gupta,S.P.Advances in QSAR studies of HIV-1 reverse transcriptase inhibitors.Prog.Drug Res.2002,58,223-264.
[12]Kounim,H.Trends in the design of nucleoside analogues as anti-HIV drugs.Curr.Pharm.Des.2002,8,581-593.
[13]De Clercq,E.Antiviral drug discovery and development: Where chemistry meets with biomedicine.Antiviral.Res.2005,67,56-75.
[14]Raymond,F.S.;Brendal,H.S.;Selwyn,J.H.Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses.Antiviral Research 2006,71,322-334.
[15]Carpenter,C.C.;Cooper,D.A.;Fischl,M.A.;Gatell,J.M.Antiretro-viral therapy in adults:updated recommendations of the International Society-USA Panel.JAMA.2000,19,381-390.
[16]Erickson-Viitanen,S.;Wu,J.T.;Shi,G.;Unger,S.Cellular pharmacology of D-d4FC,a nucleoside analog active against drug-resistant HIV.Antivir.Chem.Chemother.2003,14,39-47.
[17]邓毅辉,张玲玲.抗人类免疫缺陷病毒药物及其新剂型的研究进展.中国药学杂志.2006,41,1285-1289.
[18]刘海霞,李在村,吴昊.抗HN药物的新发展.国外医学病毒学分册.2005,12,117-120.
[19]Cloud,P.A.J.Infect.,1989,18 Suppl1,15-21.
[20]Schmied,B.Reducing perinatal transmission by antiretroviral therapy.Wien.Med.Wochenschr.1998,148,550-555.
[21]Rana,K Z.;Dudley,M.N.Clinical pharmacokinetics of stavudine.Clin.Pharmacokinet.1997,33,276-284.
[22]Havlir,D.V.;Schrier,R.D.;Torriani,F.J.;Chervenak,K.;Hwang,J.Y.;Boom,W.H.
Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects.J.Infect.Dis.2000,182,321-325.
[23]Jablonowski,H.Studies of zidovudine in combination with didanosine and zalcitabine.J.Acquir.Immune.Defic.Syndr.Hum.Retrovirol.1995,10,S52-S56.
[24]Diane,V.et al.AIDS,1998,12,S 165-S 174.
[25]Johnson,M.A.et al.Clin.Pharmacokinet.1999,36,41-66.
[26]Feng,J.Y.;Shi,J.X.;Schinazi,R.F.;Anderson,K.S.Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP.J.FASEB.1999,13,1511-1517.
[27]Harvey,P.S.et al.Drugs,2000,60,447-479.
[28]Mulato,A.S.;Lamy,P.D.;Miller,M.D.;Li,W.-X.;Anton,K.E.;Hellmann,N.S.;Cherrington,J.M.Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from AIDS Patients after Prolonged Adefovir Dipivoxil Therapy.Antimicrob.Agents Chemother.1998,42,1620-1628.
[29]Silvera,P.;Racz,P.;Racz,K.;Bischofberger,N.;Crabbs,C.;Yalley-Ogunro,J.;Greenhouse,J.;Jiang,J.B.;Lewis,M.G.Effect of PMPA and PMEA on the kinetics of viral load in simian immunodeficiency virus-infected macaques.AIDS.Res.Hum.Retroviruses,2000,16,791-800.
[30]Kamp,W.;Schokker,J.;Cambridge,E.;De Jong,S.;Schuurman,R.;De Groot,T.;Boucher,C.A.Effect of weekly adefovir (PMEA)infusions on HIV-1 virus load: results of a phase Ⅰ/Ⅱstudy.Antivir.Ther.1999,4,101-107.
[31]Angtry,H.D.Drugs,1989,37: 408-450.
[32]Sperling,R.Zidovudine.Infect.Dis.Obstet.Gynecol.1998,6,197-203.
[33]Harris,M.;Montaner,J.S.G.Clinical uses of non-nucleoside reverse transcriptase inhibitors.Rev.Med.Virol.2000,10,217-229.
[34]Smith,P.F.;DiCenzo,R.;Morse,G.D.Clinical pharmacokinetics of nonnucleoside reverse transcriptase inhibitors.Clin.Pharmacokine.t,2001,40,893-905.
[35]Barreiro,P.,Soriano,V.,Blanco,F.Risks and benefits of replacing protease inhibitors by nevirapine in HIV-2 infected subjects under longterm successful triple combination therapy.AIDS.2000,14,807-812.
[36]Rober,C.HIV integrase,a brief overview from chemistry to therapeutics.Biol.Chem.2001,276,23213-23216.
[37]Boycl,M.R.;Gustafson,K.R.;Mcmahon,J.B.Discovery of cyanovirin-N,a novel human immuno deticiency virus inactivating proteint hat binds virus surface envelope gpl20:potential applications to microbicide development.J.anti-microb.Agents Chemother.1997,41,1521-1526.
[38]Jiang,S.;Zhao,Q.;Dobnath,A.K.Peptide and non-peptide HIV fusion inhibitors.Curr.Pharma.Design.2002,8.563-580.
[39]Zemlicka,J.,Enantioselectivity of the antiviral effects of nucleoside analogues.Pharmacol.Ther.2000,85,251-266.
[40]李子成,陈淑华,蒋宁.核苷类抗病毒药物的研究进展[J].化学研究与应用,2002,14,15-20.
[41]De Clercq,E.New developments in anti-HIV.Biochimica et Biophysica Acta,2002,1587,258-275.
[42]De Clercq,E.New anti-HIV angents and targets.Med.Res.Rev.,2002,22,531-565.
[43]Stella,V.J.;Himmelstein,K.J.Prodrug and site specific drug delivery.J.Med.Chem.1980,23,1275-1282.
[44]Wayne,L.Backes Prodrugs.Clin.Oncolog.Nursing.2001,5,35-38.
[45]何亮.前药的研究进展[J].世界临床药物.2006,27,55-58.
[46]Jeffrey,P.K.;Valentino,J.S.Prodrugs of phosphates,phosphonates,and phosphinates.Ad.Drug Deliver.Rev.1996,19,287-310.
[47]王淑月,王洪亮.前药原理与新药设计[M].河北工业科技,2003,20,54-57.
f48]Abraham,T.W.;Kalman,T.I.;McIntee,E.J.;Wagner,C.R.Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2'-deoxyuridine and 1-beta-arabinofuranosylcytosine: evidence of phosphoramidase activity.J.Med.Chem.1996,39,4569-4575.
[49]Fries,K.M.;Joswig,C.;Borch,R.F.Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs.J.Med.Chem.1995,38,2672-2680.
[50]Tobias,S.C.;Borch,R.F.Synthesis and Biological Studies of Novel Nucleoside Phosphoramidate Prodrugs.J.Med.Chem.2001,44,4475-4480.
[51]Caren,L.;Freel,M.;Hong,L.;Joswig,C.;Borch,R.F.Synthesis and Biological Activity of Novel 5-Fluoro-2'-deoxyuridine Phosphoramidate Prodrugs.J.Med.Chem.2000,43,4313-4318.
[52]Caren,L.;Freel,M.;Borch R.F.Activation Mechanisms of Nucleoside Phosphoramidate Prodrugs.J.Med.Chem.2000,43,4319-4327.
[53]Iyer,V.V.;Griesgraber;G.W.,Radmer,M.R.;Mclntee,E.J.;Wagner,C.R.Synthesis,in Vitro Anti-Breast Cancer Activity,and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine (AZT).J.Med.Chem.2000,43,2266-2274.
[54](a)Siddiqui,A.Q.;Ballatore,C.;McGuigan,C.;De Clercq,E.;Balzarini,J.The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship.J.Med.Chem.1999,42,393-399.(b)Balzarini,J.;Karlsson,A.;Aquaro,S.;Perno,C.F.;Cahard,D.;Naesens,L.;De Clercq,E.;McGuigan,C.Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.Proc.Natl.Acad.Sci.U.S.A.1996,93,7295-7299.
[55]Dyatkina,N.;Arzumanov,A.;Krayevsky,A.;Hara,B.O.;Gluzman,Y.;Baron,P.;MacLow,C.;Polsky,B.Nucleosides Nucleotides.1994,13,325.
[56]Egron,D.;Arzumanov,A.A.;Dyatkina,N.B.;Aubertin,A.M.;Imbach,J.L.;Gosselin,G.;Krayevsky,A.;Perigaud,C.Synthesis,Anti-HIV Activity,and Stability Studies of 5'-Phosphorofluoridate Derivatives of AZT.Bioorg.Chem.2001,29,333-344.
[57]Chang,S.L.;Griesgraber,G.W.;Southern,P.J.;Wagner,C.R.Amino Acid Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine: Relationship between Antiviral Potency and Intracellular Metabolism.J.Med.Chem.2001,44,223-231.
[58]Siddiqui,A.Q.;Ballatore,C.;McGuigan,C.;De Clercq,E.;Balzarini,J.The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship.J.Med.Chem.1999,42,393-399.
[59]Baraniak,J.;Kaczmarek,R.;Stec,W.J.Conjugation of amino acid O-methyl esters with AZT-5'-O-phosphorothioate and phosphorodithioate.Tetrahedron Lett.2000,41,9139- 9142.
[60]苗志伟.新型核苷5'-硫代磷酰氨基酸酯的合成[D].清华大学化学系.2002.
[61]Kers,I.;Girardet,J.L.;Gosselin,G.;Perigaud,C.;Imbach,J.L.;Stawinski,J.Synthesis and in vitro antiviral activity of some symmetrical phosphoramidate dimers of AZT.Nucleosides & Nucleotides.1999,18,993-994.
[62]Perigaud,C.;Gosselin,G.;Imbach,J.-L.Applying Chemical Principles to the Understanding and Treatment of Disease,John Wiley & Sons Inc.,NewYork,2000,115.
[63]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化学工业出版社.2005.
[64]梁文权.生物药剂学与药物动力学[M].北京:人民卫生出版社.2003,155.
[65]于波涛,刘文胜,蒋学华.大鼠体内快速药代动力学方法筛选潜在化合物.国外医学药学分册.2001,28,152-154.
[66]袁伯俊.新药评价基础与实践[M].北京:人 民 卫生出版社.1998,79.
[67]化学药物非临床药代动力学研究技术指导原则[S].国家食品药品监督管理局.2005.
[68]姜云云,范国荣,刘皋林.组合给药在药代动力学高通量筛选中的应用.国外医学药学分册.2005,32,38-41.
[69]Chad,L.S.;Adriaan,C.;Kjell,J.Integrated oral bioavailability projection using in vitro sereening data as a selection tool in drug discovery.Inter.J.Pharm.2004,269,241-249.
[70]安登魁.现代药物分析选论[M].北京:中国医药科技出版社.2001,575.
[71]郝光荣.实验动物学[M].上海:第二军医大学出版社.1999,113.
[72]Claire,M.;Koen,W.;Marc,H.New model for intravenous drug administration and blood sampling in the awake rat,designed to increase quality and throughput for in vivo pharmacokinetic analysis.J.Pharm.Toxic Method.2005,52,293-301.
[1]Perry,C.M.;Balfour,J.A.Didanosine: an update on its antiviral activity,pharmacokinetic properties and therapeutic efficacy in the management of HIV disease.Drugs.1996,52,928-962.
[2]Riddler,S.A.Antiretroviral activity of stavudine (2',3'-didehydro-3'-deoxythymidine,d4T).Antiviral Res.1995,27,189-203.
[3]Chen,C.H.;Vazque-Padua,M.;Cheng,Y.C.Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.Mol.Pharmacol.1991,39,625-628.
[4]Faraj,A.;Fowler,D.A.;Bridges,E.G.;Sommadossi,J.P.Effect of 2',3'-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis.Antimicrob.Agents Chemother.1994,38,924-930.
[5]Isel,C.;Ehresmann,C.;Walter,P.;Ehresmann,B.;Marquet,R.The emergence of different resistance mechanisms toward uncleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase.J.Biol.Chem.2001,276,48725-48732.
[6]Sun,X.B.;Xun,K.J.;Zhao,Y.F.One-pot synthesis of hydrogen phosphonate derivatives of d4T and AZT.Chemical Communication.2002,20,2414-2415.
[7]吴剑彬.d4T-5'-氢亚磷酸异丙酯的放大合成、性质研究及d4T-5'-氢亚磷酸酯合成方法研究[D].厦门:厦门大学化学系,2007.
[1]常雁,再帕尔·阿不力孜,王慕邹.串联质谱新技术及其中的应用进展.药学学报.2000,35,73-78.
[2]庞焕,文允锚.质谱联用技术研究进展及其在药物分析.中国药.学杂志.2001,36,433-435.
[3]Vissers,J.P.;Blackburn,R.K.;Moseley,M.A.A novel variable flow nanoscale LC/MS/MS for improved proteome coverage.J.Am.Soc.Mass.Spectrom.2002,13,760-771.
[4]Fang,N.;Yu,S.;Prior,R.L.LC/MS/MS characterization of phenolic constituents in dried Plums.J.Agric.Food Chem.2002,50,3579-3585.
[5]李关宾,李之俊,范春生.高效毛细管电泳/质谱法在线联用连结技术.分析仪器.1996,1,2.
[6]Hayen,H.;Karst,U.Strategies for the liquid chromatographic-masss spectrometric analysis of non-polar compounds.J.Chromatogr.A.2003,1000,549-565.
[7]Reemtsma,T.Liquid Chromatogarphy-mass spectrometry and strategies for trace-level analysis of polar organic pollutants.J.Chromatogr.A.2003,1000,477-501.
[8]Mellon,F.A.;Bennett,R.N.;Holst,B.Intact analysis in Plant extracts by programmed cone voltage electrospray LC/MS: performance and comparison with LC/MS/MS methods.Anal.Biochem.2002,306,83-91.
[9]Lam,W.;Ramanathan,R.In electrospary ionization source hydrogen/deuterium exchange LC-MS and LC-MS/MS for characterization of metabolites.J.Am.Soc.Mass Spectrom.2002,13,345-353.
[10]Mclafferty,F.W.Tandem Mass Spectrometry.NewYork: Wiley-Interscience.1983.
[11]李忠红,王玉,倪坤仪.LC-MS~n在药物分析中的应用.药物分析杂志.2004,24,341.
[12]Fenselau,C.Annu.Rev.Pharmacol.Toxicol.1992,32,555.
[13]Jemal,M.High-throughput quantitative bioanalysis by LC-MS/MS.Biomed.Chromatogr.2000,14,422.
[14]沈家骢,周慧,郭继芬.新型抗炎镇痛剂SFZ247在家兔体内羟基化及其结合型代谢产物的鉴定.药学学报,2000,35,181.
[15]杜宗敏,黄海华,陈笑艳.人尿中苯丙哌林羟基化代谢产物的研究.药学学报..2000,35,916-920.
[16]车庆明,黄新立,李艳梅.黄芩苷的药物代谢产物研究.中国中药杂志.2001,21,768-769.
[17]Li,Y.;Zhong,D.F.;Chen,S.W.;Maeba,I.Identification of some benproperine metabolites in humans and investigation of their antitussive effect.Acta Pharmacol.Sin.2005,26,1519-1526.
[18]Vita,M.;Abdel-Rehim,M.;Olofsson,S.;Hassna,Z.;Meurling,L.;Siden,A.;Siden,M.;Pettesrson,T.;Hassna,M.Tissue distribution,Pharmacokinetics and identification of roscovitine metabolites in rat.Eur.J.Pharm.Sci.2005,25,91-103.
[19]Shpak,A.V.;Appolonova,S.A.;Semenov,V.A.Validation of liquid chromatography-electrospray ion trap mass spectrometry method for the determination of mesocarb in human plasma and urine.J.Chromatogr.Sci.2005,43,11-2 1.
[20]Levsen,K.;Schiebel,H.M.;Behnke,B.;Dotzer,R.;Dreher,W.;Elend,M.;Thiele,H. Structure elucidation of Phase Ⅱmeatbolites by tandem mass spectrometry: an overview.J.Chromatogr.A.2005,1067,55-72.
[21]Kebarle,P.;Tnag,L.;Anal.Chem.1993,65,972-986A.
[22]King R.,Bonfiglio R.,Fernandez-Metzler C.,Miller-Stein C.,Olah T.,Mechanistic investigation of ionization suppression in electro-spray ionization.J.Am.Soc.Mass Spectrom.2000,11,942-950.
[23]Matuszewski,B.K.;Constanzer,M.L.;Chavez-Eng,C.M.Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS.Anal.Chem.2003,75,3019-3030.
[24]Bonfiglio,R;King,R.C.;Olah T.V.;Merkle,K.The effects of sample Preparation methods on the variability of the electrospray ionization response for model drug compounds.Rapid Commun.Mass Spectrom.1999,33,1175-1185.
[25]Jermal,M.;Xia,Y.Q.The need for adequate chromatographic separation in the quantitative determination of drugs in biological samples by high performance liquid chromatography with tandem mass spectrometry.Rapid Commun.Mass Spectrom.1999,13,97-106.
[26]Choi,B.K.;Hercules,D.M.;Gusev,A.I.Effect of liquid chromatography separation of complex matrices on liquid chromatography-tandem mass spectrometry signal suppression.J.Chromatogr.A.2001,907,337-342.
[27]Souverain,S.;Rudaz,S.;Veuthey,J.L.Matrix effect in LC-ESI-MS and LC-APCI-MS with off-line and on-line extraction procedures.J.Chromatogr.A.2004,1058,61-66.
[28]Charvez-Eng,C.M;Constanzer,M.L.;Matuszewski,B.K.High-performance liquid chromatographic-tandem mass spectrometric evaluation and determination of stable isotope labeled analogs of rofecoxib in human plasma samples from oral bioavailability studies.J.Chromatogr.B Analyt.Technol.Biomed.Life Sci.2002,767,117-129.
[29]Department of Health and Human Services,Food and drug administration,Guidance for Industry on Bioanalytical Method Validation.Fed.Regist,2001,66,28526.
[30]宁永成.有机化合物结构鉴定与有机波谱学.科学出版社.2000,224-265.
[31]Niessen,W.M.A.Advances in instrumentation in liquid chromatography-mass spectrometry and related liquid-introduction techniques.J.Chromatogr.A.1998,794,407-435.
[32]Wieboldt,R.;Campbell,D.A.;Henion,J.Quantitative liquid chromatographic-tandem mass spectrometric determination of orlistat in plasma with a quadrupole ion trap.J.Chromatogr.B.1998,708,121-129.
[33]Wiesner,J.L.;Sutherland F.C.W.Sensitive and rapid liquid chromatography-tandem mass spectrometry method for the determination of stavudine in human plasma.J.Chromatogr.B.2002,773,129-134.
[34]Chen,C.L.;Venkatachalam,T.K.;Zhu,Z.H.;Uckun,F.M.In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent d4T-5'-[p-bromophenyl methoxyalaninyl phosphate](Sampidine)in mice.Drug Metabolism and Disposition.2001,29,1039-1041.
[35]Fatih,M.;Sanjive,Qazi.;Sharon,P.In vivo toxicity,pharmacokinetics,and anti-human immunodeficiency virus activity of d4T-5'-[p-bromophenyl methoxyalaninyl phosphate](Sampidine)in mice.Antimicrob.Agents Chemother.2002,46,3428-3436.
[36]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化工业出版社 2005.
[37]Shah,V.P.;Midha,K.K.,Dighe,S.Analytical methods validation: bioavailability,bioequivalence and pharmacokinetics studies.J.Pharm.SCi.1992,81,309-312.
[38]Karnes,H.T.,March,C.Precision,accuracy,and data acceptance criteria in biopharmaceutical analysis.Pharm.Res.1993,10,1420-1422.
[39]萧参,陈坚行.生物药剂分析方法的认证.中国药学杂志.1993,24,425-426.
[1]Keykavous,P.,Leonard,I.W.,Edward,E.K.Novel approaches for designing 5' -O-ester prodrugs of 3’-Azido-2',3'-dideoxythymidine (AZT).Current Medicinal Chemistry.2000,7,995-1039.
[2]McGuigan,C..;Michael,P.R.;Mahmood,N.;Hay,A.J.Synthesis and anti-HIV activity of some novel diaryl phosphate derivatives of AZT.Antiviral Res.1994,24,69-77.
[3]Wagner,C.R.;Iyer,V.V.;McIntee,E.J.Pronucleotides: Toward the in vivo Delivery of Antiviral and Anticancer Nucleotides.Pronucleotides.2000,417-45 1.
[4]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化学工业出版社,2005.
[5]Shah,V.P.;Midha,K.K.,Dighe,S.Analytical methods validation: bioavailability bioequivalence and pharmacokinetics studies.J.Pharm.SCi.1992,81,309-312.
[6]Karnes,H.T.,March,C.Precision,accuracy,and data acceptance criteria in biopharmaceutical analysis.Pharm.Res.1993,10,1420-1422.
[7]萧参,陈坚行.生物药剂分析方法的认证.中国药学杂志.1993,24,425-426.
[2]周伟澄.高等药物化学选论[M].北京:化学工业出版社.2006.
[3]刘北斗.全球艾滋病流行现状.国外医学.流行病学.传染病学分册.2003,30,55.
[4]顾明,赵杰东,王彦松,段青.人免疫缺陷综合征治疗药物研究进展.西南国防医药.2005,15,107-110.
[5]Clercq,E.D.New anti-HIV agents and targets.Med.Res.Rev.2002,22.531-565.
[6]Telesnitsky,A.;Goff,S.P.Reverse transcriptase and the generation of retroviral DNA [M].//Coffin,J.M.,Hughes,S.H.,Varmu,H.E.In Retroviruses [M].New York: Cold Spring Harbor Laboratory Press,1997,121-160.
[7]Huang,H.;Choora,R.;Vervine G.L.Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance.Science,1998,282,1669-1675.
[8]Sarafianos,S.G.;Dask,Hughas,S.H.Taking aim at moving target: designing drugs to inhibit drug-resistantHIV-1 reverse transcriptases.Curr.Opin.Struct.Biol,2004,14,716-730.
[9]Nikolenko,G.N.;Frankenberry,K.A.;PALMER,S.RNase H domains obtained from treatment-experienced patients increase resistance to AZT.Antiviral.Ther.2005,10 (Suppl1),89.
[10]Sarafianos,S.G.;Clark,A.D.;Tuske S.Trapping HIV-1 reverse transcriptase before and after translocation on DNA.J.Biol.Chem.2003,278,16280-16288.
[11]Gupta,S.P.Advances in QSAR studies of HIV-1 reverse transcriptase inhibitors.Prog.Drug Res.2002,58,223-264.
[12]Kounim,H.Trends in the design of nucleoside analogues as anti-HIV drugs.Curr.Pharm.Des.2002,8,581-593.
[13]De Clercq,E.Antiviral drug discovery and development: Where chemistry meets with biomedicine.Antiviral.Res.2005,67,56-75.
[14]Raymond,F.S.;Brendal,H.S.;Selwyn,J.H.Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses.Antiviral Research 2006,71,322-334.
[15]Carpenter,C.C.;Cooper,D.A.;Fischl,M.A.;Gatell,J.M.Antiretro-viral therapy in adults:updated recommendations of the International Society-USA Panel.JAMA.2000,19,381-390.
[16]Erickson-Viitanen,S.;Wu,J.T.;Shi,G.;Unger,S.Cellular pharmacology of D-d4FC,a nucleoside analog active against drug-resistant HIV.Antivir.Chem.Chemother.2003,14,39-47.
[17]邓毅辉,张玲玲.抗人类免疫缺陷病毒药物及其新剂型的研究进展.中国药学杂志.2006,41,1285-1289.
[18]刘海霞,李在村,吴昊.抗HN药物的新发展.国外医学病毒学分册.2005,12,117-120.
[19]Cloud,P.A.J.Infect.,1989,18 Suppl1,15-21.
[20]Schmied,B.Reducing perinatal transmission by antiretroviral therapy.Wien.Med.Wochenschr.1998,148,550-555.
[21]Rana,K Z.;Dudley,M.N.Clinical pharmacokinetics of stavudine.Clin.Pharmacokinet.1997,33,276-284.
[22]Havlir,D.V.;Schrier,R.D.;Torriani,F.J.;Chervenak,K.;Hwang,J.Y.;Boom,W.H.
Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects.J.Infect.Dis.2000,182,321-325.
[23]Jablonowski,H.Studies of zidovudine in combination with didanosine and zalcitabine.J.Acquir.Immune.Defic.Syndr.Hum.Retrovirol.1995,10,S52-S56.
[24]Diane,V.et al.AIDS,1998,12,S 165-S 174.
[25]Johnson,M.A.et al.Clin.Pharmacokinet.1999,36,41-66.
[26]Feng,J.Y.;Shi,J.X.;Schinazi,R.F.;Anderson,K.S.Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP.J.FASEB.1999,13,1511-1517.
[27]Harvey,P.S.et al.Drugs,2000,60,447-479.
[28]Mulato,A.S.;Lamy,P.D.;Miller,M.D.;Li,W.-X.;Anton,K.E.;Hellmann,N.S.;Cherrington,J.M.Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from AIDS Patients after Prolonged Adefovir Dipivoxil Therapy.Antimicrob.Agents Chemother.1998,42,1620-1628.
[29]Silvera,P.;Racz,P.;Racz,K.;Bischofberger,N.;Crabbs,C.;Yalley-Ogunro,J.;Greenhouse,J.;Jiang,J.B.;Lewis,M.G.Effect of PMPA and PMEA on the kinetics of viral load in simian immunodeficiency virus-infected macaques.AIDS.Res.Hum.Retroviruses,2000,16,791-800.
[30]Kamp,W.;Schokker,J.;Cambridge,E.;De Jong,S.;Schuurman,R.;De Groot,T.;Boucher,C.A.Effect of weekly adefovir (PMEA)infusions on HIV-1 virus load: results of a phase Ⅰ/Ⅱstudy.Antivir.Ther.1999,4,101-107.
[31]Angtry,H.D.Drugs,1989,37: 408-450.
[32]Sperling,R.Zidovudine.Infect.Dis.Obstet.Gynecol.1998,6,197-203.
[33]Harris,M.;Montaner,J.S.G.Clinical uses of non-nucleoside reverse transcriptase inhibitors.Rev.Med.Virol.2000,10,217-229.
[34]Smith,P.F.;DiCenzo,R.;Morse,G.D.Clinical pharmacokinetics of nonnucleoside reverse transcriptase inhibitors.Clin.Pharmacokine.t,2001,40,893-905.
[35]Barreiro,P.,Soriano,V.,Blanco,F.Risks and benefits of replacing protease inhibitors by nevirapine in HIV-2 infected subjects under longterm successful triple combination therapy.AIDS.2000,14,807-812.
[36]Rober,C.HIV integrase,a brief overview from chemistry to therapeutics.Biol.Chem.2001,276,23213-23216.
[37]Boycl,M.R.;Gustafson,K.R.;Mcmahon,J.B.Discovery of cyanovirin-N,a novel human immuno deticiency virus inactivating proteint hat binds virus surface envelope gpl20:potential applications to microbicide development.J.anti-microb.Agents Chemother.1997,41,1521-1526.
[38]Jiang,S.;Zhao,Q.;Dobnath,A.K.Peptide and non-peptide HIV fusion inhibitors.Curr.Pharma.Design.2002,8.563-580.
[39]Zemlicka,J.,Enantioselectivity of the antiviral effects of nucleoside analogues.Pharmacol.Ther.2000,85,251-266.
[40]李子成,陈淑华,蒋宁.核苷类抗病毒药物的研究进展[J].化学研究与应用,2002,14,15-20.
[41]De Clercq,E.New developments in anti-HIV.Biochimica et Biophysica Acta,2002,1587,258-275.
[42]De Clercq,E.New anti-HIV angents and targets.Med.Res.Rev.,2002,22,531-565.
[43]Stella,V.J.;Himmelstein,K.J.Prodrug and site specific drug delivery.J.Med.Chem.1980,23,1275-1282.
[44]Wayne,L.Backes Prodrugs.Clin.Oncolog.Nursing.2001,5,35-38.
[45]何亮.前药的研究进展[J].世界临床药物.2006,27,55-58.
[46]Jeffrey,P.K.;Valentino,J.S.Prodrugs of phosphates,phosphonates,and phosphinates.Ad.Drug Deliver.Rev.1996,19,287-310.
[47]王淑月,王洪亮.前药原理与新药设计[M].河北工业科技,2003,20,54-57.
f48]Abraham,T.W.;Kalman,T.I.;McIntee,E.J.;Wagner,C.R.Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2'-deoxyuridine and 1-beta-arabinofuranosylcytosine: evidence of phosphoramidase activity.J.Med.Chem.1996,39,4569-4575.
[49]Fries,K.M.;Joswig,C.;Borch,R.F.Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs.J.Med.Chem.1995,38,2672-2680.
[50]Tobias,S.C.;Borch,R.F.Synthesis and Biological Studies of Novel Nucleoside Phosphoramidate Prodrugs.J.Med.Chem.2001,44,4475-4480.
[51]Caren,L.;Freel,M.;Hong,L.;Joswig,C.;Borch,R.F.Synthesis and Biological Activity of Novel 5-Fluoro-2'-deoxyuridine Phosphoramidate Prodrugs.J.Med.Chem.2000,43,4313-4318.
[52]Caren,L.;Freel,M.;Borch R.F.Activation Mechanisms of Nucleoside Phosphoramidate Prodrugs.J.Med.Chem.2000,43,4319-4327.
[53]Iyer,V.V.;Griesgraber;G.W.,Radmer,M.R.;Mclntee,E.J.;Wagner,C.R.Synthesis,in Vitro Anti-Breast Cancer Activity,and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine (AZT).J.Med.Chem.2000,43,2266-2274.
[54](a)Siddiqui,A.Q.;Ballatore,C.;McGuigan,C.;De Clercq,E.;Balzarini,J.The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship.J.Med.Chem.1999,42,393-399.(b)Balzarini,J.;Karlsson,A.;Aquaro,S.;Perno,C.F.;Cahard,D.;Naesens,L.;De Clercq,E.;McGuigan,C.Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives.Proc.Natl.Acad.Sci.U.S.A.1996,93,7295-7299.
[55]Dyatkina,N.;Arzumanov,A.;Krayevsky,A.;Hara,B.O.;Gluzman,Y.;Baron,P.;MacLow,C.;Polsky,B.Nucleosides Nucleotides.1994,13,325.
[56]Egron,D.;Arzumanov,A.A.;Dyatkina,N.B.;Aubertin,A.M.;Imbach,J.L.;Gosselin,G.;Krayevsky,A.;Perigaud,C.Synthesis,Anti-HIV Activity,and Stability Studies of 5'-Phosphorofluoridate Derivatives of AZT.Bioorg.Chem.2001,29,333-344.
[57]Chang,S.L.;Griesgraber,G.W.;Southern,P.J.;Wagner,C.R.Amino Acid Phosphoramidate Monoesters of 3'-Azido-3'-deoxythymidine: Relationship between Antiviral Potency and Intracellular Metabolism.J.Med.Chem.2001,44,223-231.
[58]Siddiqui,A.Q.;Ballatore,C.;McGuigan,C.;De Clercq,E.;Balzarini,J.The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture: A Structure-Activity Relationship.J.Med.Chem.1999,42,393-399.
[59]Baraniak,J.;Kaczmarek,R.;Stec,W.J.Conjugation of amino acid O-methyl esters with AZT-5'-O-phosphorothioate and phosphorodithioate.Tetrahedron Lett.2000,41,9139- 9142.
[60]苗志伟.新型核苷5'-硫代磷酰氨基酸酯的合成[D].清华大学化学系.2002.
[61]Kers,I.;Girardet,J.L.;Gosselin,G.;Perigaud,C.;Imbach,J.L.;Stawinski,J.Synthesis and in vitro antiviral activity of some symmetrical phosphoramidate dimers of AZT.Nucleosides & Nucleotides.1999,18,993-994.
[62]Perigaud,C.;Gosselin,G.;Imbach,J.-L.Applying Chemical Principles to the Understanding and Treatment of Disease,John Wiley & Sons Inc.,NewYork,2000,115.
[63]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化学工业出版社.2005.
[64]梁文权.生物药剂学与药物动力学[M].北京:人民卫生出版社.2003,155.
[65]于波涛,刘文胜,蒋学华.大鼠体内快速药代动力学方法筛选潜在化合物.国外医学药学分册.2001,28,152-154.
[66]袁伯俊.新药评价基础与实践[M].北京:人 民 卫生出版社.1998,79.
[67]化学药物非临床药代动力学研究技术指导原则[S].国家食品药品监督管理局.2005.
[68]姜云云,范国荣,刘皋林.组合给药在药代动力学高通量筛选中的应用.国外医学药学分册.2005,32,38-41.
[69]Chad,L.S.;Adriaan,C.;Kjell,J.Integrated oral bioavailability projection using in vitro sereening data as a selection tool in drug discovery.Inter.J.Pharm.2004,269,241-249.
[70]安登魁.现代药物分析选论[M].北京:中国医药科技出版社.2001,575.
[71]郝光荣.实验动物学[M].上海:第二军医大学出版社.1999,113.
[72]Claire,M.;Koen,W.;Marc,H.New model for intravenous drug administration and blood sampling in the awake rat,designed to increase quality and throughput for in vivo pharmacokinetic analysis.J.Pharm.Toxic Method.2005,52,293-301.
[1]Perry,C.M.;Balfour,J.A.Didanosine: an update on its antiviral activity,pharmacokinetic properties and therapeutic efficacy in the management of HIV disease.Drugs.1996,52,928-962.
[2]Riddler,S.A.Antiretroviral activity of stavudine (2',3'-didehydro-3'-deoxythymidine,d4T).Antiviral Res.1995,27,189-203.
[3]Chen,C.H.;Vazque-Padua,M.;Cheng,Y.C.Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.Mol.Pharmacol.1991,39,625-628.
[4]Faraj,A.;Fowler,D.A.;Bridges,E.G.;Sommadossi,J.P.Effect of 2',3'-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis.Antimicrob.Agents Chemother.1994,38,924-930.
[5]Isel,C.;Ehresmann,C.;Walter,P.;Ehresmann,B.;Marquet,R.The emergence of different resistance mechanisms toward uncleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase.J.Biol.Chem.2001,276,48725-48732.
[6]Sun,X.B.;Xun,K.J.;Zhao,Y.F.One-pot synthesis of hydrogen phosphonate derivatives of d4T and AZT.Chemical Communication.2002,20,2414-2415.
[7]吴剑彬.d4T-5'-氢亚磷酸异丙酯的放大合成、性质研究及d4T-5'-氢亚磷酸酯合成方法研究[D].厦门:厦门大学化学系,2007.
[1]常雁,再帕尔·阿不力孜,王慕邹.串联质谱新技术及其中的应用进展.药学学报.2000,35,73-78.
[2]庞焕,文允锚.质谱联用技术研究进展及其在药物分析.中国药.学杂志.2001,36,433-435.
[3]Vissers,J.P.;Blackburn,R.K.;Moseley,M.A.A novel variable flow nanoscale LC/MS/MS for improved proteome coverage.J.Am.Soc.Mass.Spectrom.2002,13,760-771.
[4]Fang,N.;Yu,S.;Prior,R.L.LC/MS/MS characterization of phenolic constituents in dried Plums.J.Agric.Food Chem.2002,50,3579-3585.
[5]李关宾,李之俊,范春生.高效毛细管电泳/质谱法在线联用连结技术.分析仪器.1996,1,2.
[6]Hayen,H.;Karst,U.Strategies for the liquid chromatographic-masss spectrometric analysis of non-polar compounds.J.Chromatogr.A.2003,1000,549-565.
[7]Reemtsma,T.Liquid Chromatogarphy-mass spectrometry and strategies for trace-level analysis of polar organic pollutants.J.Chromatogr.A.2003,1000,477-501.
[8]Mellon,F.A.;Bennett,R.N.;Holst,B.Intact analysis in Plant extracts by programmed cone voltage electrospray LC/MS: performance and comparison with LC/MS/MS methods.Anal.Biochem.2002,306,83-91.
[9]Lam,W.;Ramanathan,R.In electrospary ionization source hydrogen/deuterium exchange LC-MS and LC-MS/MS for characterization of metabolites.J.Am.Soc.Mass Spectrom.2002,13,345-353.
[10]Mclafferty,F.W.Tandem Mass Spectrometry.NewYork: Wiley-Interscience.1983.
[11]李忠红,王玉,倪坤仪.LC-MS~n在药物分析中的应用.药物分析杂志.2004,24,341.
[12]Fenselau,C.Annu.Rev.Pharmacol.Toxicol.1992,32,555.
[13]Jemal,M.High-throughput quantitative bioanalysis by LC-MS/MS.Biomed.Chromatogr.2000,14,422.
[14]沈家骢,周慧,郭继芬.新型抗炎镇痛剂SFZ247在家兔体内羟基化及其结合型代谢产物的鉴定.药学学报,2000,35,181.
[15]杜宗敏,黄海华,陈笑艳.人尿中苯丙哌林羟基化代谢产物的研究.药学学报..2000,35,916-920.
[16]车庆明,黄新立,李艳梅.黄芩苷的药物代谢产物研究.中国中药杂志.2001,21,768-769.
[17]Li,Y.;Zhong,D.F.;Chen,S.W.;Maeba,I.Identification of some benproperine metabolites in humans and investigation of their antitussive effect.Acta Pharmacol.Sin.2005,26,1519-1526.
[18]Vita,M.;Abdel-Rehim,M.;Olofsson,S.;Hassna,Z.;Meurling,L.;Siden,A.;Siden,M.;Pettesrson,T.;Hassna,M.Tissue distribution,Pharmacokinetics and identification of roscovitine metabolites in rat.Eur.J.Pharm.Sci.2005,25,91-103.
[19]Shpak,A.V.;Appolonova,S.A.;Semenov,V.A.Validation of liquid chromatography-electrospray ion trap mass spectrometry method for the determination of mesocarb in human plasma and urine.J.Chromatogr.Sci.2005,43,11-2 1.
[20]Levsen,K.;Schiebel,H.M.;Behnke,B.;Dotzer,R.;Dreher,W.;Elend,M.;Thiele,H. Structure elucidation of Phase Ⅱmeatbolites by tandem mass spectrometry: an overview.J.Chromatogr.A.2005,1067,55-72.
[21]Kebarle,P.;Tnag,L.;Anal.Chem.1993,65,972-986A.
[22]King R.,Bonfiglio R.,Fernandez-Metzler C.,Miller-Stein C.,Olah T.,Mechanistic investigation of ionization suppression in electro-spray ionization.J.Am.Soc.Mass Spectrom.2000,11,942-950.
[23]Matuszewski,B.K.;Constanzer,M.L.;Chavez-Eng,C.M.Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS.Anal.Chem.2003,75,3019-3030.
[24]Bonfiglio,R;King,R.C.;Olah T.V.;Merkle,K.The effects of sample Preparation methods on the variability of the electrospray ionization response for model drug compounds.Rapid Commun.Mass Spectrom.1999,33,1175-1185.
[25]Jermal,M.;Xia,Y.Q.The need for adequate chromatographic separation in the quantitative determination of drugs in biological samples by high performance liquid chromatography with tandem mass spectrometry.Rapid Commun.Mass Spectrom.1999,13,97-106.
[26]Choi,B.K.;Hercules,D.M.;Gusev,A.I.Effect of liquid chromatography separation of complex matrices on liquid chromatography-tandem mass spectrometry signal suppression.J.Chromatogr.A.2001,907,337-342.
[27]Souverain,S.;Rudaz,S.;Veuthey,J.L.Matrix effect in LC-ESI-MS and LC-APCI-MS with off-line and on-line extraction procedures.J.Chromatogr.A.2004,1058,61-66.
[28]Charvez-Eng,C.M;Constanzer,M.L.;Matuszewski,B.K.High-performance liquid chromatographic-tandem mass spectrometric evaluation and determination of stable isotope labeled analogs of rofecoxib in human plasma samples from oral bioavailability studies.J.Chromatogr.B Analyt.Technol.Biomed.Life Sci.2002,767,117-129.
[29]Department of Health and Human Services,Food and drug administration,Guidance for Industry on Bioanalytical Method Validation.Fed.Regist,2001,66,28526.
[30]宁永成.有机化合物结构鉴定与有机波谱学.科学出版社.2000,224-265.
[31]Niessen,W.M.A.Advances in instrumentation in liquid chromatography-mass spectrometry and related liquid-introduction techniques.J.Chromatogr.A.1998,794,407-435.
[32]Wieboldt,R.;Campbell,D.A.;Henion,J.Quantitative liquid chromatographic-tandem mass spectrometric determination of orlistat in plasma with a quadrupole ion trap.J.Chromatogr.B.1998,708,121-129.
[33]Wiesner,J.L.;Sutherland F.C.W.Sensitive and rapid liquid chromatography-tandem mass spectrometry method for the determination of stavudine in human plasma.J.Chromatogr.B.2002,773,129-134.
[34]Chen,C.L.;Venkatachalam,T.K.;Zhu,Z.H.;Uckun,F.M.In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent d4T-5'-[p-bromophenyl methoxyalaninyl phosphate](Sampidine)in mice.Drug Metabolism and Disposition.2001,29,1039-1041.
[35]Fatih,M.;Sanjive,Qazi.;Sharon,P.In vivo toxicity,pharmacokinetics,and anti-human immunodeficiency virus activity of d4T-5'-[p-bromophenyl methoxyalaninyl phosphate](Sampidine)in mice.Antimicrob.Agents Chemother.2002,46,3428-3436.
[36]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化工业出版社 2005.
[37]Shah,V.P.;Midha,K.K.,Dighe,S.Analytical methods validation: bioavailability,bioequivalence and pharmacokinetics studies.J.Pharm.SCi.1992,81,309-312.
[38]Karnes,H.T.,March,C.Precision,accuracy,and data acceptance criteria in biopharmaceutical analysis.Pharm.Res.1993,10,1420-1422.
[39]萧参,陈坚行.生物药剂分析方法的认证.中国药学杂志.1993,24,425-426.
[1]Keykavous,P.,Leonard,I.W.,Edward,E.K.Novel approaches for designing 5' -O-ester prodrugs of 3’-Azido-2',3'-dideoxythymidine (AZT).Current Medicinal Chemistry.2000,7,995-1039.
[2]McGuigan,C..;Michael,P.R.;Mahmood,N.;Hay,A.J.Synthesis and anti-HIV activity of some novel diaryl phosphate derivatives of AZT.Antiviral Res.1994,24,69-77.
[3]Wagner,C.R.;Iyer,V.V.;McIntee,E.J.Pronucleotides: Toward the in vivo Delivery of Antiviral and Anticancer Nucleotides.Pronucleotides.2000,417-45 1.
[4]王广基,刘晓东,刘晓泉.药物代谢动力学[M].北京:化学工业出版社,2005.
[5]Shah,V.P.;Midha,K.K.,Dighe,S.Analytical methods validation: bioavailability bioequivalence and pharmacokinetics studies.J.Pharm.SCi.1992,81,309-312.
[6]Karnes,H.T.,March,C.Precision,accuracy,and data acceptance criteria in biopharmaceutical analysis.Pharm.Res.1993,10,1420-1422.
[7]萧参,陈坚行.生物药剂分析方法的认证.中国药学杂志.1993,24,425-426.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |