药物代谢性质（ADME）早期快速预测技术的研究及系列化合物的评价
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摘要
随着组合化学和高通量筛选技术的发展，药物研发速度发生了质的飞跃，但其中40％化合物会因代谢性质较差而被淘汰。本课题的目的就是为了紧跟国际前沿和加快国内创制新药的步伐，在两项基金的资助下，率先在国内建立起快速的早期药代预测体系，解决关键技术，推动药物研发进程。
整个课题研究内容分为两大部分：遵循快速、简单、通用、有效的原则，首先建立了计算机虚拟、体外及体内三个层次快速药代性质预测模型；进而应用该体系对几个创新系列化合物进行筛选，得到了一些结构-代谢效应关系的规律，评选出几个有开发前景的候选药物，并验证了不同模型之间的相关性。
模型构建：
计算机虚拟预测采用VolSurf及Pallas软件。先用已知的阳性结果验证软件的预测能力，其中Caco-2细胞透膜性及血脑屏障通透性都与文献报道的结果有较好的相关性，相关系数分别为r~2=0.8998，r~2=0.7714。我们还应用VolSurf软件首次构建了预测P-gp的底物模型。通过模型提供的信息，得出一些有意义的结论：1．化合物大小、形状及容量性质与P-gp ATP酶活性成正相关；2．化合物的POL(极性)和氢键容量(HB)也明显影响P-gp ATP酶活性；3．P-gp底物可能具有两亲性。
在体外快速预测技术中，我们用阳性药物作为质控标准构建了国际公认的用于大量化合物透膜性质评价的Caco-2细胞模型、人工膜模型和用于评价代谢稳定性的肝微粒体模型，为了提高体外评价的通量，还在人工膜模型和肝微粒体模型上建立了盒式多药(n in one)筛选技术。
在体内快速评价技术中，建立了整体动物同时给多个药物(盒式给药)，并与单独给药的结果进行比较，发现两种给药方式的药代动力学参数没有明显的差别。在生物利用度的快速评价中，采用多次采血，一次测定的实验方法“一点法”，比较同系列化合物的生物利用度，结果与传统方法的生物利用度排序基本一致。
药物评价：
对AGEs裂解剂系列化合物从计算机、体外、体内三个层次进行了评价。通过对计算机预测结果与结构进行比较发现：化合物的透膜性主要与临界堆积参数和D(疏水探针与靶标分子相互作用产生的疏水性区域)成正比，而C_w(容量因子，亲水区／分子表面积)与其成反比。在体外实验中，分别应用Caco-2细胞、人工膜模型、肝微粒体模型进行评价，并考察了计算机、Caco-2细胞模型评价结果的相关性。
With the development of Combinatorial Chemistry and high throughput screening technology, the speed of drug discovery has improved dramatically. However, it has been estimated that approximately 40% of compounds have failed in the past due to problems in pharmacokinetics and drug delivery. The objective of this paper was to in pace with the latest development of international pharmaceutical industry and to accelerate the national drug research. Surported by two foundations, we have taken the lead in constructing a systematic screening system and established the key technology to speed up the development of drug discovery.
This dissertation consists of two parts. Firstly, in accordance with the principle of rapidness, simplicity, generality and effectiveness, an integrated screening ADME properties system including three phases of in silico, in vitro and in vivo was constructed. Secondly, we evaluated several series of novel compounds by using the platform and validated the relationships among different models.
Model Construction:
VolSurf and Pallas soft wares were applied in computational prediction. As the first step, we validated the predictive ability of these soft wares by using the known compounds published on literature or from our past experiments. Liner regression analysis showed a reasonable correlation (r~2=0.8998, r~2=0.7714). A new two components partial least squares discriminant analysis (PLS) model for the prediction of P-glycoprotein-associated ATPase activity of drugs was built by using VolSurf compute theoretical molecule descriptors derived from 3D molecule interaction fields. The results effectively investigated that properties associated with the volume, polarizability, and hydrogen bond could have important impact on the P-glycoprotein-associated ATPase activity.
On in vitro ADME screening system, Caco-2 cell model and PAMPA model were built to evaluate the permeability, and liver microsome model was developed to appraise the metabolic stability. We optimized the experimental conditions to standardize the models. In order to increase the in vitro throughput, 5 in 1 approach in PAMPA and liver
整个课题研究内容分为两大部分：遵循快速、简单、通用、有效的原则，首先建立了计算机虚拟、体外及体内三个层次快速药代性质预测模型；进而应用该体系对几个创新系列化合物进行筛选，得到了一些结构-代谢效应关系的规律，评选出几个有开发前景的候选药物，并验证了不同模型之间的相关性。
模型构建：
计算机虚拟预测采用VolSurf及Pallas软件。先用已知的阳性结果验证软件的预测能力，其中Caco-2细胞透膜性及血脑屏障通透性都与文献报道的结果有较好的相关性，相关系数分别为r~2=0.8998，r~2=0.7714。我们还应用VolSurf软件首次构建了预测P-gp的底物模型。通过模型提供的信息，得出一些有意义的结论：1．化合物大小、形状及容量性质与P-gp ATP酶活性成正相关；2．化合物的POL(极性)和氢键容量(HB)也明显影响P-gp ATP酶活性；3．P-gp底物可能具有两亲性。
在体外快速预测技术中，我们用阳性药物作为质控标准构建了国际公认的用于大量化合物透膜性质评价的Caco-2细胞模型、人工膜模型和用于评价代谢稳定性的肝微粒体模型，为了提高体外评价的通量，还在人工膜模型和肝微粒体模型上建立了盒式多药(n in one)筛选技术。
在体内快速评价技术中，建立了整体动物同时给多个药物(盒式给药)，并与单独给药的结果进行比较，发现两种给药方式的药代动力学参数没有明显的差别。在生物利用度的快速评价中，采用多次采血，一次测定的实验方法“一点法”，比较同系列化合物的生物利用度，结果与传统方法的生物利用度排序基本一致。
药物评价：
对AGEs裂解剂系列化合物从计算机、体外、体内三个层次进行了评价。通过对计算机预测结果与结构进行比较发现：化合物的透膜性主要与临界堆积参数和D(疏水探针与靶标分子相互作用产生的疏水性区域)成正比，而C_w(容量因子，亲水区／分子表面积)与其成反比。在体外实验中，分别应用Caco-2细胞、人工膜模型、肝微粒体模型进行评价，并考察了计算机、Caco-2细胞模型评价结果的相关性。
With the development of Combinatorial Chemistry and high throughput screening technology, the speed of drug discovery has improved dramatically. However, it has been estimated that approximately 40% of compounds have failed in the past due to problems in pharmacokinetics and drug delivery. The objective of this paper was to in pace with the latest development of international pharmaceutical industry and to accelerate the national drug research. Surported by two foundations, we have taken the lead in constructing a systematic screening system and established the key technology to speed up the development of drug discovery.
This dissertation consists of two parts. Firstly, in accordance with the principle of rapidness, simplicity, generality and effectiveness, an integrated screening ADME properties system including three phases of in silico, in vitro and in vivo was constructed. Secondly, we evaluated several series of novel compounds by using the platform and validated the relationships among different models.
Model Construction:
VolSurf and Pallas soft wares were applied in computational prediction. As the first step, we validated the predictive ability of these soft wares by using the known compounds published on literature or from our past experiments. Liner regression analysis showed a reasonable correlation (r~2=0.8998, r~2=0.7714). A new two components partial least squares discriminant analysis (PLS) model for the prediction of P-glycoprotein-associated ATPase activity of drugs was built by using VolSurf compute theoretical molecule descriptors derived from 3D molecule interaction fields. The results effectively investigated that properties associated with the volume, polarizability, and hydrogen bond could have important impact on the P-glycoprotein-associated ATPase activity.
On in vitro ADME screening system, Caco-2 cell model and PAMPA model were built to evaluate the permeability, and liver microsome model was developed to appraise the metabolic stability. We optimized the experimental conditions to standardize the models. In order to increase the in vitro throughput, 5 in 1 approach in PAMPA and liver
引文
[1] Tarbit MH, Berman J. High-throughput approaches for evaluating absorption, distraction, metabolism, and excretion properties of lead compounds. Curr. Opin. Chem. Biol., 1998, 2: 411-416.
[2] Hodgson J. ADMET-turning chemicals into drugs. Nat Biotechnol. 2001,19:722-726
[3] Hansch C, Quantitative relationships between lipophilic character and drug metabolism. Drug Metab. Rev., 1972, 1: 1 -14.
[4] Suzuki A., Higuchi, W.I., Ho, N.F., Theoretical model studies of drug absorption and transport in the gastrointestinal tract II. J. Pharm. Sci. 1970. 59: 651-659.
[5] Ho N.F., Higuchi W.I., Tun J. Theoretical model studies of drug absorption and transport in the GI tract (3). J. Pharm. Sci. 1972, 61:192-197.
[6] Dressman, J.B., Amidon, G.L., Fleisher, D., Absorption potential: estimating the fraction absorbed for orally administered compounds. J. Pharm. Sci. 1985, 74: 588-589.[7] Boxenbaum H. Absorption potential and its variants. Pharm. Res. 1999, 16: 1893
[8] Boobis, A. et al. In silico prediction of ADME and pharmacokinetics report of an expert meeting organised by COST B15. Eur. J. Pharma. Sci. 2002,17: 183-193.
[9] Lombardo, F., Obach, R.S., Shalaeva, M.Y., Gao, F., Prediction o volume of distribution values in humans for neutral and basic drug using physicochemical measurements and plasma protein binding data. J. Med. Chem. 2002,45: 2867-2876.
[10] Ekins, S., Waler, C.L., Swaan, P.W., Cruciani, G., Wrighton, S.A., Wikel, J.H., Progress in predicting human ADME parameters in silico. J. Pharmacol. Toxicol. Methods 2000,44: 251-272.
[11] TerLaak, A.M.,Vermeulen, N.P.E., Molecular modeling approaches to predict drug metabolism and toxicity: a summary. In: Testa, B., van de Waterbeemd, H., Folkers, G., Guy, R. (Eds.), Pharmacokinetic Optimization in Drug Research—Biological, Physicochemical and Computational Strategies. Wiley-VCH, Helvetica Chimica Acta, Zurich, 2001. pp. 551-588.[12] Cruiani G, Manuel P, Wolfgang G VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. Europ J Pharm Sci, 2000,11 (Suppl 2): S29-S39
[13] Cramer, R. D. III, Patterson, D. E., & Bunce, J. D.. Comparative molecular field analysis (CoMFA): 1. Effect of shape on binding of steroids to carrier proteins. J Am. Chem. Soci 1988110: 5959- 5967.
[14] Lene HA, Inge TC, Anders B, Maria S, Lars H, Sven F. Structure-Property model for membrane partitioning of oligopenptides. J Med. Chem., 2000,43(1): 103-113.
[15].Rene H, Jan H. Successful in silico predicting of intestinal lymphatic transfer. Int J Pharmaceu, 2004,272(1-2): 189-193.
[16] Ismael J, Hidalgo, Thomas J, Raub, Ronald T, Borchardt. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology, 1989, 96(6):736-749
[17] Lenz, K., Aungst, B., Iioyd, T, Baulgarelli, J., Tweed, J., Mourin, M., An automated system for maintaining Caco-2 cell cultures and performing HT permeability screening. In : International Symposium on Laboratory Automation and Robotics, Boston, MA
[18] Liang E., Chessic, K., Yazdanian, M., Evaluation of an accelerated Caco-2 cell permeability model. J. Pharm. Sci. 2000, 89(3): 336.
[19] Kansy, M., Senner, F., Gubernator, K., Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 1998, 41: 1007-1010
[20] Ong S, Liu H, Qiu X., Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces. Anal. Chem., 1995,67(4): 755-756
[21] Nakagawa Y, Suzuki T. Metabolism of bisphenol A in isolated rat hepatocytes and oesteogenic activity of a hydroxylated metabolite in MCF-7 human breast cancer cells. Xenobiotica, 2001,31(3): 113-125
[22] Alexander VK, Amit SK, Anthony M, Robert SC, Theodore EL. Pharmacokinetics and metabolism of A cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats :in vitro-in vivo correlation, gender related??differences, isoform identification and comparison with metabolism in human hepatic tissue. Drug Metab Disp, 2001,29(11): 1403-1409
[23] Smith DA, van de Waterbeemd H. Pharmacokinetics and metabolism in early drug discovery. Curr. Opin. Chem. Biol. 1999,3:373-378
[24] Lin, J. H., & Lu, A. Y. H.. Inhibition of cytochrome P-450 and implications in drug development. Annual Reports in Medicinal Chemistry, 1997,32: 295-304.
[25] Bock, K. W., Gschaidmeier, H., Heel, H., Lehmkoster, T., Munzel, P. A., & Bock-Hennig, B. S. Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyl-transferases. Drug Meta. Rev., 1999,31: 411-422.
[26] Audus, K.L., Borchardt, R.T., Characterization of an in vitro blood-brain barrier model system for studying drug transport and metabolism, Pharmaceutical Res. 1986,3: 81-87.
[27] K. A. Stanness, E. Guatteo, D. Janigro, A dynamic model of the blood-brain barrier 'in vitro', NeuroToxicology 1996,17(2): 481-496.
[28] Garrigues A., Nugier J., Orlowski S., Ezan E., A High-Throughput Screening Microplate Test for the Interaction of Drugs with P-Glycoprotein Ana.Biochem. 2002,305: 106-114
[29] Litman, T., Zeuthen, T., Skovsgaard, T., and Stein, W. D. Competitive, nonconpetitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim. Biophys. Acta 1997,1361: 169-176.
[30] Berman J., Halm, K., Adkison, K., Simultaneous pharmacokinetic screening of a compounds in the dog using API LC/MS/MS analysis for increased throughput. J Med. Chem, 1997, 40: 827-829.
[31] Allen MC, Shan TS., Day WW., Rapid determination of oral pharmacokinetics and plasma free fraction using cocktail approaches: methods and application. Pharm. Res., 1998, 15: 93-97.
[32] Bayliss MK., Frick LW. High-throughput pharmacokinetics: cassette dosing. Curr. Opin. Drug Disco. Devel. 1999, 2: 20-25.
[33] Kuo BS., Van, Noord T., Feng, MR., Sample pooling to expedite bioanalysis and pharmacokinetic research. J Pharm. Biomed Anal. 1998,16: 837-846.[34] Cox, KA., Dunn-Meynell, K., Korfmacher, WA., Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats. Drug Discov.Today, 1999, 4: 232-237
[35] Volmer DA., Hui, JPM., Rapid SPME/MS/MS analysis of N-methylcarbamate pesticides in water. Arch Environ. Contam. Toxicol. 1998, 35: 1-7.
[36] Cheng YF., Neue UD., Bean L., Straight forward solid-phase extraction method for the determination of verapamil and its metabolite in plasma in a 96-well extraction plate. J. Chromatogr A1998,828: 273-281.
[37] Jemal M., Qing, Y., Whigan DB., The use of high-fliw performance liquid chromatography coupled with positive and negative ion electrospray tandem mass spectrometry for quantitative bilanalysis via direct injection of the plasma /serum samples. Rapid Commun. Mass Spectrom. 1998,12: 1389-1399.
[38] SjOberg P. MolSurf - a generator of chemical descriptors for QSAR. In: Van de waterbeemd H, Testa B, Folkers G, eds. Computer-Assisted Lead Finding and Optimization: Current Tools for Medical Chemistry. Basel: VHCA (Verlag. Helvetica Chimica Acta), 1997,5: 83-92.
[39] Goodford PJ. A computational procedure for determining energetically favourable binding sites on biologically important macromolecules. J Med Chem. 1985,28(7): 849-857
[40] Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA). 1.Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc, 1988,110(18): 5959-5967.
[41] Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G, Beigi, F., Lundahl, P., & Artursson, P., Evaluation of dynamic polar molecular surface area as a predictor of drug absorption: comparison with other computational and experimental predictors. J. Med. Chem. 1998,41: 5382-5392.
[42] Luco, J.M., Prediction of the brain-blood distribution of a large set of drugs from structurally derived descriptors using partial least squares (PLS) modeling. J. Chem. Inf. Comput. Sci. 1999, 39: 396-404
[43] Litman, T., Zeuthen, T., Skovsgaard, T., Stein, W.D., Structure-activity??relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity. Biochim. Biophys. Acta 1997,1361: 159-168.
[44] Osterberg, T., Norinder, U., Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization PLS statistics. Eur. J. Pharm. Sci. 2000,10: 295-303.
[45] Orlowski, S., Garrigos, M., Multiple recognition of various amphiphilic molecules by the multidrug resistance P-glycoprotein: molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs. Anticancer Res. 1999,19: 3109-3123.
[46] Garrigues, A., Nugier, J., Orlowski, S., Ezan, E.,. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal. Biochem. 2002,305:106-114.
[47] Seelig, A.,. A general pattern for substrate recognition by Pglycoprotein. Eur. J. Biochem. 1998,251: 252-261.
[48] Andrej Bugrim, Tatiana Nikolskaya and Yuri Nikolsky, Early prediction of drug metabolism and toxicity: systems biology approach and modeling DDT. 2004, 9: 127-135.
[49] Brown, A. C, & Fraser, T. R. On the connection between chemical constitution and physiological action. Transactions of the Royal Society of Edinburgh. 1868: 25, 151-203,693-739.
[50] Lipinski CA, Lombardo F, Dominy BW, Paul J, Feeney. Experimental estimation of the effective unstirred water layer thickness in the human jejunum and its importance in oral drug absorption. Adv. Drug Delivery Rev. 1997, 23(1-3): 3-25.
[51] Romiti, N., Tramonti, G., Donati, A., Chieli, E. Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2. Life Sci. 2004, 76: 293-302.
[52] Ambudkar, S.V., Dey, S., Hrycyna, C.A., Ramachandra, M., Pastan, I., Gottesman, M.M., Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 1999,39: 361-398.
[53] Schinkel, A.H., The physiological function of drug-transporting Pglycoproteins.??Semin. Cancer Biol. 1997,8: 161-170.
[54] Gaasterland, T. and Selkov, E. Reconstruction of metabolic networks using incomplete information. Proc. Int. Conf. Intell. Syst. Mol.Biol. 1995, 3:127-135
[55] Hansch, C, Mekapati, SB, Kurup, A. and Verma, RP. "QSAR of cytochrome P450", Drug Metab. Rev. 2004,36:105-156.
[56] Artursson, P., & Karlsson, J.. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys.l Res.Commun. 1991,175: 880- 885.
[57] Blais, A.,Bissonnette, P., Berteloot, A., Correlation between oral drug absorption in human and apparent drug permeability coefficients in human intestinal epithelial (Caco-2 )cells. Biochem. Biophys.Res. 1995,175: 113-125
[58] Hidalgo, IJ., Raub, T.J, Borchardt, R.T., Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology, 1989, 96: 736-749.
[59] Hidalgo, IJ., Borchardt, R.T. Transport of bile acids in a human intestinal epithelial cell line. Caco-2 Biochim. Biophys. Acta.1990, 1035: 97-103
[60] Praveen V. Balimane, Karishma Patel, Anthony Marino, Saeho Chong Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery. Eur J Pharmace. Biopharma 2004, 58: 99-105
[61] Walle UK, Galijatovic A., Walle T. Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2. Biochem. Pharmacol. 1999b, 58:431-438
[62] Yamashita, S., Furubayashi, T. Kataoka, M., Toshiyasu S. Hitoshi, S. Hideaki T. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur. J. Pharmaceu. Sci. 2000, 10: 195-204
[63] Hilgers, A.R., Conradi, R.A., Burton, P.S., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm. Res. 1990, 7: 902-910.
[64] Clony PC, Neutra, MR., Epithelial differentiation in the fetal rat colon. I. Plasma membrane phosphatase acticities.1983, 97: 349-363.
[65] Stewart, WW., Functional connections between cells as revealed by dye-coupling ??with a highly fluorescent naphthalimide tracer. Cell 1978,14: 741-759.
[66] Gopal Krishna, Kwang-jong Chen, Chin-chung Lin, Amin A. Nomeir Permeability of lipophilic compounds in drug discovery using in-vitro human absorption model, Caco-2. Int. J Pharmaceu. 2001,222: 77-89.
[67] E. Duizer , A.H. Penninks, W.H. Stenhuis, J.P. Groten Comparison of permeability characteristics of the human colonic Caco-2 and rat small intestinal IEC-18 cell lines. J. Con. Release. 1997,49: 39-49.
[68] Kim, M., Kometani, T., Okada, S., Shimiau, M, Permeation of hesperidin glycosides across Caco-2 cell monolayers via the paracellular pathway. Biosci. Biotechnol. Biochem. 1999,63: 2183-2188.
[69] Hai Tal Y., Guang Ji W. Transport and uptake characteristics of a new derivative of berberine (CPU -86017) by human intestinal epithelial cell line: Caco-2. Acta Pharmacol Sin 2003, 24: 1185-1191.
[70] M. Markowska, R. Oberle, S. Juzwin, C.-P. Hsu, M. Gryszkiewicz, A.J. Streeter, Optimizing caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis. J. Pharmacol. Toxicol. Methods, 2001,46: 51-55.
[71] Di, L., Kerns, E.H., Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. 2003, 7: 402-408.
[72] Ruell, J., Membrane-based drug assays, Mod. Drug Disc, 2003,1: 28-30.
[73] Instruction manual for PSR4p permeability analyzer, Rev., 1.4.4. pION INC Woburn, Massachusetts, 2001
[74] Thomas O., John, L., Dan, S. Automated Multiscreen PAMPA and permeability assay system, www: millipore .com
[75] Veber, D.F., Johnson, S.R., Cheng, H.-Y., Smith, B.R., Ward, K.W., Kopple, K.D., Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002,45: 2615-2623.
[76] Lake, BG, Preparation and characterization of microsomal fractions for studies on xenobiotic metabolism, in Biochemical Toxicology, A Practical Approach. IRL Press Oxford., 1987, Snell K and Mullock B eds pp 183-215.
[77] Lowry OH, Rosebrough J, Farr AL, Randall RJ. Protein measurement with the Folin ??phenol reagent. J Biol Res. 1951,193: 265-269.
[78] Omura T, Sato R. The carbon monoxide binding pigment of liver microsomes. Evidence for its hemoprotein nature. J Biol Chem. 1964,239:2370-2373.
[79] Kelly M. Jenkins, Reginald Angeles, Marianne T. Quintos, Rongda Xu, Daniel B. Kassel, Robyn A. Rourick Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J Pharmace. Biomed. Ana. 2004, 34: 989-1004.
[80] Dear GJ, Fraser TJ, Patel DK, Long J, Pleasance S. Use of liquid chromatographyitandem mass spectrometry for the quantitative and qualitative analysis of an antipsychotic agent and its metabolites in human plasma and urine. J Chromatogr A 1998, 794:27-36.
[81] M. Markowska, R. Oberle, S. Juzwin, C.-P. Hsu, M. Gryszkiewicz, A. J. Streeter, Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis, J. Pharmacol. Toxicol. Methods 2001,46: 51-55.
[82] C. Tannergren, P. Langguth, K.J. Hoffman, Compound mixtures in Caco-2 cell permeability screens as a means to increase screening capacity, Pharmazie 2001,56: 337-342.
[83] Hsieh, Y. Direct cocktail analysis of drug discovery compounds in pooled plasma samples using liquid chromatographytandem mass spectrometry. J. Chromatog. B. Analyt. Technol. Biomed. Life Sci. 2002,767: 353-362.
[84] Rounald E.W., Prasarn, M., Pharmacokinetic theory of cassette dosing in drug discovery screening. Drug Metab. Disp. 2001,29: 957-966.
[85] N. F. Smith A. Hayes B. P. Nutley F. I. Raynaud P. Workman Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice. Cancer. Chemother. Pharmacol. 2004, 54: 475 - 486.
[86] Ron Huang, Mark Qian, Susan Chen, Peter Lodenquai, Hang Zeng, Jing-Tao Wu Effective strategies for the development of specific, sensitive and rapid multiple-component assays for cassette dosing pharmacokinetic screening. Int. J. Mass Spectrometry. 2004,238: 131-137.
[87] Kathleen A. C, Ronald E. W. Walter A. K. Rapid Determination of??Pharmacokinetic Properties of New Chemical Entities: In vivo Approaches Combinatorial Chemistry & High Throughput Screening, 2002, 5: 29-37.
[88] Walter A. K., Kathleen A. C., Kwokei J. N, John V., Yunsheng H., Sam W., Lisa B, Dan P., Amin N., Ronald E. White Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem massspectrometric analysis of new chemical entities as part of new drug discovery Rapid Commun. Mass Spectrom. 2001, 15: 335-340.
[89] Prasarn M. and Ronald E.W., Whatever happened to cassette dosing pharmacokinetics? DDT 2004, 9: 652-658.
[90] Hop C. E. C. A.; Wang, Z.; Chen, Qing; Kwei, G. Plasma-Pooling Methods to Increase Throughput for In Vivo Pharmacokinetic Screening. J. Pharm. Sci. 1998, 87: 901-903.
[91] Chad L. S., Adriaan C., Kjell J.c, Doo-Man O., Hussein H., Joanne B. Narayanan S., Hyo-Kyung H., Integrated oral bioavailability projection using in vitroscreening data as a selection tool in drug discovery Int J. Pharmace. 2004, 269: 241-249.
[92] Castellani, RJ., Harris, PLR., Sayre LM., et al. Active Glycation in neurofibrillary pathology of Alzheimer's disease: ne(Carboxymethl)lysine and hexitol-lysine. Free Rad. Biol. Med. 2001, 31(2): 175-180.
[93] Averdano GF. Agarwal PK., Bashey RI., et al. Effect of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes. 1999, 48: 1443-1447.
[94] Wolffenbuttel BH. Boulargen CM., Crijns FR., et al. Breakers of advanced glycation end products restore large arterg properties in experimental diabete. Proc. Natl. Acad. Sci. U.S.A. 1998, 95: 4603-4634
[95] Vassans Zhang X., Kapurniotu A. et al. An agent cleaving glycose-derived protein cross-link in vitro and in vivo. Nature. 1996, 382: 275-278.
[96] 王海龙．液相色谱—离子阱质谱技术在胍丁胺、CNT-986和AGEs裂解剂代谢研究中的应用．军事医学科学院．硕士学位论文．2005，44-46．
[97] Patel J, Hussain A, Pal D, Mitra AK. A mathematical simulation to explain the coordinated functions of efflux and metabolism limiting the transport of anti-HIV??agents across Caco-2 cells. Am J Ther, 2004, 11(2): 114-123.
[98] Yamashita S, Furubayashi T, Kataoka M, et al. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci. 2000, 10(3): 195-204.
[99] Walter E, Kissel T. Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport. Eur J Pharm Sci. 1995, 3(4): 215-230.
[100] Albert P.L. Screening for human ADME/Tox drug properties in drug discovery. DDT 2001, 6: 357-366.
[101] Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. & Imanaka, H. FK505, A novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J. Antibiotics(Tokyo) 1987, 40: 1249-1255.
[102] M.P. Dehouck, P. Jolliet-Riant, F. Bree, J.C. Fruchart, R. Cecchelli, J.P. Tillement, Drug transfert across the blood-brain barrier: correlation between in vitro and in vivo models, J. Neurochem. 1992, 58: 1790-1797.
[103] 周婷，谢蓝．HIV非核苷类逆转录酶抑制剂研究进展．Acta Pharmaceutica Sinica 2004，39：666-672．
[104] Okada K., Sakura Y., Kawaji H., et al. Regression of rat mammary tumors by a potent luteinizing hormone-releasing hormone analogue(Leuprolide) administered vaginally. Cancer Res. 1983, 43: 1869-b1874.
[105] Murphy, A.T. Berna M.J., Holsapple J.L., Ackermann B.L.Effects of flow rate on high-throughput quantitative analysis of protein-precipitated plasma using liquid chromatography/tandem mass spectrometry Rapid Commun. Mass Spectrom. 2002, 16: 537-543.
[106] 肖琳琳．胍丁胺临床前药代动力学及其衍生物早期评价．军事医学科学院硕士论文．2006，5：48
[107] Suhonen, T.M., Pasonen-Seppanen, S., Kirjavainen, M., Tammi, M., Tammi, R., Urtti, A.,. The permeability barrier in organotypic culture model derived from rat epidermal keratinocytes. Eur. J. Pharm. Sci. 2003, 20: 107-113.
[108] Toropainen, E., Ranta, V.P., Palmgren, J., Vellonen, K.S., Talvitie, A., Suhonen, P.,??Hamalainen, K.M., Auriola, S., Urtti, A., Paracellular and transcellular permeability in human corneal epithelial cell culture model. Eur. J. Pharm. Sci. 2003,20: 99-106.
[109] Avdeef, A., Strafford, M., Block, E., Balogh, M.P., Chambliss, W., Khan, I.,. Drug absorption in vitro model: filter immobilized artificial membranes. 2. Studies of the permeability properties of lactones in Piper methysticum. Forst. Eur. J. Pharm. Sci. 2001, 14: 271-280.
[110] Norris, D. A., Leesman, G. D., Sinko, P. J., & Grass, G. M. Development of predictive phamacokinetic simulation models for drug discovery. Journal of Controlled Release, 2000,65: 55-62.
[111] Yee, S., In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man: fact or myth. Pharm. Res. 1997,14: 763-766.
[112] Artursson, P., Borchardt, R.T., Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm. Res. 1997,14: 1655-1658.
[113] L. Laitinen, H. Kangas, A.M. Kaukonen, K. Hakala, T. Kotiaho, R. Kostiainen, J. Hirvonen, N-in-one permeability studies of heterogenous sets of compounds across caco-2 cell monolayers, Pharm. Res. 20 (2003) 187-197.
[114] P. Larger, M. Altamura, R.M. Catalioto, S. Giuliani, C.-A. Maggi, C. Valenti, A. Triolo, Simultaneous LC-MS/MS determination of reference pharmaceuticals as a method for the characterization of caco-2 cell monolayer absorption properties, Anal. Chem. 2002,7: 5273-5281.
[2] Hodgson J. ADMET-turning chemicals into drugs. Nat Biotechnol. 2001,19:722-726
[3] Hansch C, Quantitative relationships between lipophilic character and drug metabolism. Drug Metab. Rev., 1972, 1: 1 -14.
[4] Suzuki A., Higuchi, W.I., Ho, N.F., Theoretical model studies of drug absorption and transport in the gastrointestinal tract II. J. Pharm. Sci. 1970. 59: 651-659.
[5] Ho N.F., Higuchi W.I., Tun J. Theoretical model studies of drug absorption and transport in the GI tract (3). J. Pharm. Sci. 1972, 61:192-197.
[6] Dressman, J.B., Amidon, G.L., Fleisher, D., Absorption potential: estimating the fraction absorbed for orally administered compounds. J. Pharm. Sci. 1985, 74: 588-589.[7] Boxenbaum H. Absorption potential and its variants. Pharm. Res. 1999, 16: 1893
[8] Boobis, A. et al. In silico prediction of ADME and pharmacokinetics report of an expert meeting organised by COST B15. Eur. J. Pharma. Sci. 2002,17: 183-193.
[9] Lombardo, F., Obach, R.S., Shalaeva, M.Y., Gao, F., Prediction o volume of distribution values in humans for neutral and basic drug using physicochemical measurements and plasma protein binding data. J. Med. Chem. 2002,45: 2867-2876.
[10] Ekins, S., Waler, C.L., Swaan, P.W., Cruciani, G., Wrighton, S.A., Wikel, J.H., Progress in predicting human ADME parameters in silico. J. Pharmacol. Toxicol. Methods 2000,44: 251-272.
[11] TerLaak, A.M.,Vermeulen, N.P.E., Molecular modeling approaches to predict drug metabolism and toxicity: a summary. In: Testa, B., van de Waterbeemd, H., Folkers, G., Guy, R. (Eds.), Pharmacokinetic Optimization in Drug Research—Biological, Physicochemical and Computational Strategies. Wiley-VCH, Helvetica Chimica Acta, Zurich, 2001. pp. 551-588.[12] Cruiani G, Manuel P, Wolfgang G VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. Europ J Pharm Sci, 2000,11 (Suppl 2): S29-S39
[13] Cramer, R. D. III, Patterson, D. E., & Bunce, J. D.. Comparative molecular field analysis (CoMFA): 1. Effect of shape on binding of steroids to carrier proteins. J Am. Chem. Soci 1988110: 5959- 5967.
[14] Lene HA, Inge TC, Anders B, Maria S, Lars H, Sven F. Structure-Property model for membrane partitioning of oligopenptides. J Med. Chem., 2000,43(1): 103-113.
[15].Rene H, Jan H. Successful in silico predicting of intestinal lymphatic transfer. Int J Pharmaceu, 2004,272(1-2): 189-193.
[16] Ismael J, Hidalgo, Thomas J, Raub, Ronald T, Borchardt. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology, 1989, 96(6):736-749
[17] Lenz, K., Aungst, B., Iioyd, T, Baulgarelli, J., Tweed, J., Mourin, M., An automated system for maintaining Caco-2 cell cultures and performing HT permeability screening. In : International Symposium on Laboratory Automation and Robotics, Boston, MA
[18] Liang E., Chessic, K., Yazdanian, M., Evaluation of an accelerated Caco-2 cell permeability model. J. Pharm. Sci. 2000, 89(3): 336.
[19] Kansy, M., Senner, F., Gubernator, K., Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 1998, 41: 1007-1010
[20] Ong S, Liu H, Qiu X., Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces. Anal. Chem., 1995,67(4): 755-756
[21] Nakagawa Y, Suzuki T. Metabolism of bisphenol A in isolated rat hepatocytes and oesteogenic activity of a hydroxylated metabolite in MCF-7 human breast cancer cells. Xenobiotica, 2001,31(3): 113-125
[22] Alexander VK, Amit SK, Anthony M, Robert SC, Theodore EL. Pharmacokinetics and metabolism of A cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats :in vitro-in vivo correlation, gender related??differences, isoform identification and comparison with metabolism in human hepatic tissue. Drug Metab Disp, 2001,29(11): 1403-1409
[23] Smith DA, van de Waterbeemd H. Pharmacokinetics and metabolism in early drug discovery. Curr. Opin. Chem. Biol. 1999,3:373-378
[24] Lin, J. H., & Lu, A. Y. H.. Inhibition of cytochrome P-450 and implications in drug development. Annual Reports in Medicinal Chemistry, 1997,32: 295-304.
[25] Bock, K. W., Gschaidmeier, H., Heel, H., Lehmkoster, T., Munzel, P. A., & Bock-Hennig, B. S. Functions and transcriptional regulation of PAH-inducible human UDP-glucuronosyl-transferases. Drug Meta. Rev., 1999,31: 411-422.
[26] Audus, K.L., Borchardt, R.T., Characterization of an in vitro blood-brain barrier model system for studying drug transport and metabolism, Pharmaceutical Res. 1986,3: 81-87.
[27] K. A. Stanness, E. Guatteo, D. Janigro, A dynamic model of the blood-brain barrier 'in vitro', NeuroToxicology 1996,17(2): 481-496.
[28] Garrigues A., Nugier J., Orlowski S., Ezan E., A High-Throughput Screening Microplate Test for the Interaction of Drugs with P-Glycoprotein Ana.Biochem. 2002,305: 106-114
[29] Litman, T., Zeuthen, T., Skovsgaard, T., and Stein, W. D. Competitive, nonconpetitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim. Biophys. Acta 1997,1361: 169-176.
[30] Berman J., Halm, K., Adkison, K., Simultaneous pharmacokinetic screening of a compounds in the dog using API LC/MS/MS analysis for increased throughput. J Med. Chem, 1997, 40: 827-829.
[31] Allen MC, Shan TS., Day WW., Rapid determination of oral pharmacokinetics and plasma free fraction using cocktail approaches: methods and application. Pharm. Res., 1998, 15: 93-97.
[32] Bayliss MK., Frick LW. High-throughput pharmacokinetics: cassette dosing. Curr. Opin. Drug Disco. Devel. 1999, 2: 20-25.
[33] Kuo BS., Van, Noord T., Feng, MR., Sample pooling to expedite bioanalysis and pharmacokinetic research. J Pharm. Biomed Anal. 1998,16: 837-846.[34] Cox, KA., Dunn-Meynell, K., Korfmacher, WA., Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats. Drug Discov.Today, 1999, 4: 232-237
[35] Volmer DA., Hui, JPM., Rapid SPME/MS/MS analysis of N-methylcarbamate pesticides in water. Arch Environ. Contam. Toxicol. 1998, 35: 1-7.
[36] Cheng YF., Neue UD., Bean L., Straight forward solid-phase extraction method for the determination of verapamil and its metabolite in plasma in a 96-well extraction plate. J. Chromatogr A1998,828: 273-281.
[37] Jemal M., Qing, Y., Whigan DB., The use of high-fliw performance liquid chromatography coupled with positive and negative ion electrospray tandem mass spectrometry for quantitative bilanalysis via direct injection of the plasma /serum samples. Rapid Commun. Mass Spectrom. 1998,12: 1389-1399.
[38] SjOberg P. MolSurf - a generator of chemical descriptors for QSAR. In: Van de waterbeemd H, Testa B, Folkers G, eds. Computer-Assisted Lead Finding and Optimization: Current Tools for Medical Chemistry. Basel: VHCA (Verlag. Helvetica Chimica Acta), 1997,5: 83-92.
[39] Goodford PJ. A computational procedure for determining energetically favourable binding sites on biologically important macromolecules. J Med Chem. 1985,28(7): 849-857
[40] Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA). 1.Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc, 1988,110(18): 5959-5967.
[41] Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G, Beigi, F., Lundahl, P., & Artursson, P., Evaluation of dynamic polar molecular surface area as a predictor of drug absorption: comparison with other computational and experimental predictors. J. Med. Chem. 1998,41: 5382-5392.
[42] Luco, J.M., Prediction of the brain-blood distribution of a large set of drugs from structurally derived descriptors using partial least squares (PLS) modeling. J. Chem. Inf. Comput. Sci. 1999, 39: 396-404
[43] Litman, T., Zeuthen, T., Skovsgaard, T., Stein, W.D., Structure-activity??relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity. Biochim. Biophys. Acta 1997,1361: 159-168.
[44] Osterberg, T., Norinder, U., Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization PLS statistics. Eur. J. Pharm. Sci. 2000,10: 295-303.
[45] Orlowski, S., Garrigos, M., Multiple recognition of various amphiphilic molecules by the multidrug resistance P-glycoprotein: molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs. Anticancer Res. 1999,19: 3109-3123.
[46] Garrigues, A., Nugier, J., Orlowski, S., Ezan, E.,. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal. Biochem. 2002,305:106-114.
[47] Seelig, A.,. A general pattern for substrate recognition by Pglycoprotein. Eur. J. Biochem. 1998,251: 252-261.
[48] Andrej Bugrim, Tatiana Nikolskaya and Yuri Nikolsky, Early prediction of drug metabolism and toxicity: systems biology approach and modeling DDT. 2004, 9: 127-135.
[49] Brown, A. C, & Fraser, T. R. On the connection between chemical constitution and physiological action. Transactions of the Royal Society of Edinburgh. 1868: 25, 151-203,693-739.
[50] Lipinski CA, Lombardo F, Dominy BW, Paul J, Feeney. Experimental estimation of the effective unstirred water layer thickness in the human jejunum and its importance in oral drug absorption. Adv. Drug Delivery Rev. 1997, 23(1-3): 3-25.
[51] Romiti, N., Tramonti, G., Donati, A., Chieli, E. Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2. Life Sci. 2004, 76: 293-302.
[52] Ambudkar, S.V., Dey, S., Hrycyna, C.A., Ramachandra, M., Pastan, I., Gottesman, M.M., Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 1999,39: 361-398.
[53] Schinkel, A.H., The physiological function of drug-transporting Pglycoproteins.??Semin. Cancer Biol. 1997,8: 161-170.
[54] Gaasterland, T. and Selkov, E. Reconstruction of metabolic networks using incomplete information. Proc. Int. Conf. Intell. Syst. Mol.Biol. 1995, 3:127-135
[55] Hansch, C, Mekapati, SB, Kurup, A. and Verma, RP. "QSAR of cytochrome P450", Drug Metab. Rev. 2004,36:105-156.
[56] Artursson, P., & Karlsson, J.. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys.l Res.Commun. 1991,175: 880- 885.
[57] Blais, A.,Bissonnette, P., Berteloot, A., Correlation between oral drug absorption in human and apparent drug permeability coefficients in human intestinal epithelial (Caco-2 )cells. Biochem. Biophys.Res. 1995,175: 113-125
[58] Hidalgo, IJ., Raub, T.J, Borchardt, R.T., Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology, 1989, 96: 736-749.
[59] Hidalgo, IJ., Borchardt, R.T. Transport of bile acids in a human intestinal epithelial cell line. Caco-2 Biochim. Biophys. Acta.1990, 1035: 97-103
[60] Praveen V. Balimane, Karishma Patel, Anthony Marino, Saeho Chong Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery. Eur J Pharmace. Biopharma 2004, 58: 99-105
[61] Walle UK, Galijatovic A., Walle T. Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2. Biochem. Pharmacol. 1999b, 58:431-438
[62] Yamashita, S., Furubayashi, T. Kataoka, M., Toshiyasu S. Hitoshi, S. Hideaki T. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur. J. Pharmaceu. Sci. 2000, 10: 195-204
[63] Hilgers, A.R., Conradi, R.A., Burton, P.S., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm. Res. 1990, 7: 902-910.
[64] Clony PC, Neutra, MR., Epithelial differentiation in the fetal rat colon. I. Plasma membrane phosphatase acticities.1983, 97: 349-363.
[65] Stewart, WW., Functional connections between cells as revealed by dye-coupling ??with a highly fluorescent naphthalimide tracer. Cell 1978,14: 741-759.
[66] Gopal Krishna, Kwang-jong Chen, Chin-chung Lin, Amin A. Nomeir Permeability of lipophilic compounds in drug discovery using in-vitro human absorption model, Caco-2. Int. J Pharmaceu. 2001,222: 77-89.
[67] E. Duizer , A.H. Penninks, W.H. Stenhuis, J.P. Groten Comparison of permeability characteristics of the human colonic Caco-2 and rat small intestinal IEC-18 cell lines. J. Con. Release. 1997,49: 39-49.
[68] Kim, M., Kometani, T., Okada, S., Shimiau, M, Permeation of hesperidin glycosides across Caco-2 cell monolayers via the paracellular pathway. Biosci. Biotechnol. Biochem. 1999,63: 2183-2188.
[69] Hai Tal Y., Guang Ji W. Transport and uptake characteristics of a new derivative of berberine (CPU -86017) by human intestinal epithelial cell line: Caco-2. Acta Pharmacol Sin 2003, 24: 1185-1191.
[70] M. Markowska, R. Oberle, S. Juzwin, C.-P. Hsu, M. Gryszkiewicz, A.J. Streeter, Optimizing caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis. J. Pharmacol. Toxicol. Methods, 2001,46: 51-55.
[71] Di, L., Kerns, E.H., Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. 2003, 7: 402-408.
[72] Ruell, J., Membrane-based drug assays, Mod. Drug Disc, 2003,1: 28-30.
[73] Instruction manual for PSR4p permeability analyzer, Rev., 1.4.4. pION INC Woburn, Massachusetts, 2001
[74] Thomas O., John, L., Dan, S. Automated Multiscreen PAMPA and permeability assay system, www: millipore .com
[75] Veber, D.F., Johnson, S.R., Cheng, H.-Y., Smith, B.R., Ward, K.W., Kopple, K.D., Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002,45: 2615-2623.
[76] Lake, BG, Preparation and characterization of microsomal fractions for studies on xenobiotic metabolism, in Biochemical Toxicology, A Practical Approach. IRL Press Oxford., 1987, Snell K and Mullock B eds pp 183-215.
[77] Lowry OH, Rosebrough J, Farr AL, Randall RJ. Protein measurement with the Folin ??phenol reagent. J Biol Res. 1951,193: 265-269.
[78] Omura T, Sato R. The carbon monoxide binding pigment of liver microsomes. Evidence for its hemoprotein nature. J Biol Chem. 1964,239:2370-2373.
[79] Kelly M. Jenkins, Reginald Angeles, Marianne T. Quintos, Rongda Xu, Daniel B. Kassel, Robyn A. Rourick Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J Pharmace. Biomed. Ana. 2004, 34: 989-1004.
[80] Dear GJ, Fraser TJ, Patel DK, Long J, Pleasance S. Use of liquid chromatographyitandem mass spectrometry for the quantitative and qualitative analysis of an antipsychotic agent and its metabolites in human plasma and urine. J Chromatogr A 1998, 794:27-36.
[81] M. Markowska, R. Oberle, S. Juzwin, C.-P. Hsu, M. Gryszkiewicz, A. J. Streeter, Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis, J. Pharmacol. Toxicol. Methods 2001,46: 51-55.
[82] C. Tannergren, P. Langguth, K.J. Hoffman, Compound mixtures in Caco-2 cell permeability screens as a means to increase screening capacity, Pharmazie 2001,56: 337-342.
[83] Hsieh, Y. Direct cocktail analysis of drug discovery compounds in pooled plasma samples using liquid chromatographytandem mass spectrometry. J. Chromatog. B. Analyt. Technol. Biomed. Life Sci. 2002,767: 353-362.
[84] Rounald E.W., Prasarn, M., Pharmacokinetic theory of cassette dosing in drug discovery screening. Drug Metab. Disp. 2001,29: 957-966.
[85] N. F. Smith A. Hayes B. P. Nutley F. I. Raynaud P. Workman Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice. Cancer. Chemother. Pharmacol. 2004, 54: 475 - 486.
[86] Ron Huang, Mark Qian, Susan Chen, Peter Lodenquai, Hang Zeng, Jing-Tao Wu Effective strategies for the development of specific, sensitive and rapid multiple-component assays for cassette dosing pharmacokinetic screening. Int. J. Mass Spectrometry. 2004,238: 131-137.
[87] Kathleen A. C, Ronald E. W. Walter A. K. Rapid Determination of??Pharmacokinetic Properties of New Chemical Entities: In vivo Approaches Combinatorial Chemistry & High Throughput Screening, 2002, 5: 29-37.
[88] Walter A. K., Kathleen A. C., Kwokei J. N, John V., Yunsheng H., Sam W., Lisa B, Dan P., Amin N., Ronald E. White Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem massspectrometric analysis of new chemical entities as part of new drug discovery Rapid Commun. Mass Spectrom. 2001, 15: 335-340.
[89] Prasarn M. and Ronald E.W., Whatever happened to cassette dosing pharmacokinetics? DDT 2004, 9: 652-658.
[90] Hop C. E. C. A.; Wang, Z.; Chen, Qing; Kwei, G. Plasma-Pooling Methods to Increase Throughput for In Vivo Pharmacokinetic Screening. J. Pharm. Sci. 1998, 87: 901-903.
[91] Chad L. S., Adriaan C., Kjell J.c, Doo-Man O., Hussein H., Joanne B. Narayanan S., Hyo-Kyung H., Integrated oral bioavailability projection using in vitroscreening data as a selection tool in drug discovery Int J. Pharmace. 2004, 269: 241-249.
[92] Castellani, RJ., Harris, PLR., Sayre LM., et al. Active Glycation in neurofibrillary pathology of Alzheimer's disease: ne(Carboxymethl)lysine and hexitol-lysine. Free Rad. Biol. Med. 2001, 31(2): 175-180.
[93] Averdano GF. Agarwal PK., Bashey RI., et al. Effect of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes. 1999, 48: 1443-1447.
[94] Wolffenbuttel BH. Boulargen CM., Crijns FR., et al. Breakers of advanced glycation end products restore large arterg properties in experimental diabete. Proc. Natl. Acad. Sci. U.S.A. 1998, 95: 4603-4634
[95] Vassans Zhang X., Kapurniotu A. et al. An agent cleaving glycose-derived protein cross-link in vitro and in vivo. Nature. 1996, 382: 275-278.
[96] 王海龙．液相色谱—离子阱质谱技术在胍丁胺、CNT-986和AGEs裂解剂代谢研究中的应用．军事医学科学院．硕士学位论文．2005，44-46．
[97] Patel J, Hussain A, Pal D, Mitra AK. A mathematical simulation to explain the coordinated functions of efflux and metabolism limiting the transport of anti-HIV??agents across Caco-2 cells. Am J Ther, 2004, 11(2): 114-123.
[98] Yamashita S, Furubayashi T, Kataoka M, et al. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci. 2000, 10(3): 195-204.
[99] Walter E, Kissel T. Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport. Eur J Pharm Sci. 1995, 3(4): 215-230.
[100] Albert P.L. Screening for human ADME/Tox drug properties in drug discovery. DDT 2001, 6: 357-366.
[101] Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. & Imanaka, H. FK505, A novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J. Antibiotics(Tokyo) 1987, 40: 1249-1255.
[102] M.P. Dehouck, P. Jolliet-Riant, F. Bree, J.C. Fruchart, R. Cecchelli, J.P. Tillement, Drug transfert across the blood-brain barrier: correlation between in vitro and in vivo models, J. Neurochem. 1992, 58: 1790-1797.
[103] 周婷，谢蓝．HIV非核苷类逆转录酶抑制剂研究进展．Acta Pharmaceutica Sinica 2004，39：666-672．
[104] Okada K., Sakura Y., Kawaji H., et al. Regression of rat mammary tumors by a potent luteinizing hormone-releasing hormone analogue(Leuprolide) administered vaginally. Cancer Res. 1983, 43: 1869-b1874.
[105] Murphy, A.T. Berna M.J., Holsapple J.L., Ackermann B.L.Effects of flow rate on high-throughput quantitative analysis of protein-precipitated plasma using liquid chromatography/tandem mass spectrometry Rapid Commun. Mass Spectrom. 2002, 16: 537-543.
[106] 肖琳琳．胍丁胺临床前药代动力学及其衍生物早期评价．军事医学科学院硕士论文．2006，5：48
[107] Suhonen, T.M., Pasonen-Seppanen, S., Kirjavainen, M., Tammi, M., Tammi, R., Urtti, A.,. The permeability barrier in organotypic culture model derived from rat epidermal keratinocytes. Eur. J. Pharm. Sci. 2003, 20: 107-113.
[108] Toropainen, E., Ranta, V.P., Palmgren, J., Vellonen, K.S., Talvitie, A., Suhonen, P.,??Hamalainen, K.M., Auriola, S., Urtti, A., Paracellular and transcellular permeability in human corneal epithelial cell culture model. Eur. J. Pharm. Sci. 2003,20: 99-106.
[109] Avdeef, A., Strafford, M., Block, E., Balogh, M.P., Chambliss, W., Khan, I.,. Drug absorption in vitro model: filter immobilized artificial membranes. 2. Studies of the permeability properties of lactones in Piper methysticum. Forst. Eur. J. Pharm. Sci. 2001, 14: 271-280.
[110] Norris, D. A., Leesman, G. D., Sinko, P. J., & Grass, G. M. Development of predictive phamacokinetic simulation models for drug discovery. Journal of Controlled Release, 2000,65: 55-62.
[111] Yee, S., In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man: fact or myth. Pharm. Res. 1997,14: 763-766.
[112] Artursson, P., Borchardt, R.T., Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm. Res. 1997,14: 1655-1658.
[113] L. Laitinen, H. Kangas, A.M. Kaukonen, K. Hakala, T. Kotiaho, R. Kostiainen, J. Hirvonen, N-in-one permeability studies of heterogenous sets of compounds across caco-2 cell monolayers, Pharm. Res. 20 (2003) 187-197.
[114] P. Larger, M. Altamura, R.M. Catalioto, S. Giuliani, C.-A. Maggi, C. Valenti, A. Triolo, Simultaneous LC-MS/MS determination of reference pharmaceuticals as a method for the characterization of caco-2 cell monolayer absorption properties, Anal. Chem. 2002,7: 5273-5281.