Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Elshaer, Amr
Languages: English
Types: Doctoral thesis
Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1.1. Introduction……………………………………………………..……………………….……………………………………30
    • 1.2. Biopharmaceutical classification system…………………..…………………….………………………………30
    • Diluents……………………………………………………………..…………………………………………….………37
    • Binders………………………………………………………………..…………………………………………..……37
    • Glidants………………………………………………………………………………………………………..…………38
    • Tablet characterisation………………………………………………………………………………………………39
    • P-glycoprotein. …………………………………………………..………………………….…………………52
    • Manius, G. J. (1978). Trimethoprim, In K. Florey (ed.), Analytical profiles of drug substances, vol. 7 Academic Press: New York. 445-475
    • Marat, M., Ni, A.L., Yu, X., Oko, Y., Smith, R., Argraves., B., (2008). ATP-binding cassette transporters ABCA1, ABCA7, and ABCG1 in mouse spermatozoa., Biochemical and Biophysical Research Communications. 376, 472-477
    • Martin, Y.C. (1981). A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry. J. Med. Chem. 24, 229-237.
    • Martinez, M.N., Amidon, G.L., (2002). A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals, Pharmacokinet. Pharmacodyn. 42, 620- 643.
    • Marquez, B., Nancy, E., Caceres, Marie-Paule Mingeot-Leclercq, Paul M. Tulkens, Franc¸oise Van BambekeStudies with Ciprofloxacin-Resistant Cells Ciprofloxacin in Murine Macrophages: the Fluoroquinolone Antibiotic Identification Antimicrob. Agents Chemother. 2009, 5, 36.
    • Matter K., Balda M. S., (2003). Signalling to and from tight junctions., Nature Reviews Molecular Cell Biology. 4, 225-237.
    • McEwan, G.T., Lucas, M.L., (1990). The effect of E. coli STa enterotoxin on the absorption of weakly dissociable drugs from rat proximal jejunum in vivo. Br. J. Pharmacol. 101, 937-943
    • Mehran Yazdanian, Susan L. Glynn, James L. (1998). Wright and Amale HawiCorrelating Partitioning and Caco-2 Cell Permeability of Structurally Diverse Small Molecular Weight Compounds., Pharm. Res. 15, (9) 1490-1494.
    • Meshi, T., and Sato, Y. (1972). Studies on sulfamethoxazole-trimethoprim. Absorption, distribution, excretion and metabolism of trimethoprim in rat. Chem. Pharm. Bull. 20, 2079- 2090.
    • Metz, R., Soergel, F. (1990). The gastrointestinal secretion of quinolones, Preliminary evaluation of in vivo animal model. 3rd International Symposium of New Quinolones, July 12- 14, Vancouver, Canada.
    • Meyerhoffer, M., McGown, LB., (1990) Critical micelle concentration behavior of sodium
    • Miller, J. M., Dahan, A., Gupta, D., Varghese, S., Amidon, G. L. (2009). Quasi-Equilibrium Analysis of the Ion-Pair Mediated Membrane Transport of Low-Permeability Drugs. J. Controlled Release. 137, 31-37.
    • Mitchell, B.E, Jurs, P.C., (1998). Prediction of Aqueous Solubility of Organic Compounds from Molecular Structure., J. Chem. Inf. Comput. Sci. 38, 489-496
    • Mordelle, A S., Jullian, E., Costa, C., Cormet-Boyaka, E., Benamouzic, R .,Tome, D., (2000). EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line. Am J Physiol Gastrointest Liver Physiol. 279, 366-373.
    • Morales CR, Ni X, Smith CE, Inagaki N, (2012). Hermo LABCA17 mediates sterol efflux from mouse spermatozoa plasma membranes. Histol Histopathol. 27, 3, 317-328.
    • Murakami., T. Takano M. (2008). Intestinal efflux transporters and drug absorption. Expert Opin Drug Metab Toxicol 4, 7, 923-939
    • Naggar, V.F., (1981). An in vitro study of the interaction between diazepam and some antacids or excipients. Pharmazie. 36, 114-117.
    • Nakano, M., (1971). Effects of interaction with surfactants, adsorbents, and other substances on the permeation of chlorpromazine through a dimethyl polysiloxane membrane. J. Pharm. Sci. 60, 571-575.
    • Naramoto H, Uematsu T, Uchihashi T, Doto R, Matsuura T, et al. (2007). Multidrug resistanceassociated protein 7 expression is involved in crossresistance to docetaxel in salivary gland adenocarcinoma cell lines. Int J Oncol. 30, 2, 393-401.
    • Neuhoff , S., Ungell, A., Zamora I., Artursson., P., (2005). pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers., Eur. J. Pharm. Sci. 25, 211-220
    • Neuman, M. (1988). Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin. Pharmacokin. 14, 96-121
    • Newton, J. M., Cook, . D. T., Hollebon, C. E., (1977). The strength of tablets of mixed components. J. Pharm. Pharmacol. 29, 247-249.
    • Nimmerfall, F., Rosenthaler, J. (1980). Dependence of area under the curve on proquazone particle size and in vitro dissolution rate. J. Pharm. Sci. 69, 605-607.
    • Noyes, A.A., Whitney, W.R., (1897). The rate of solution of solid substances in their own solutions. J. Am. Chem. Soc. 19 930-934.
    • Nystrom, C. Karehill, P., (1995). Importance of intermolecular bonding forces and the concept of bonding surface area. eds Goran Alderborn and Christer Nystrom, pharmaceutical powder compaction technology, Drugs and pharmaceutical sciences; volume 71 Marcel Dekker: New York.
    • Ogura, K., Kobayashi, M., Nakayama, M., Miho, Y., (1998). Electrochemical and in situ FTIR studies on the adsorption and oxidation of glycine and lysine in alkaline medium., Journal of Electroanalytical Chemistry. 449, 101-109
    • Olivera, M.E., Manzo, R.H., Junginger, H.E., Midha, K.K., Shah, V.P., Stavchansky, S., Dressman, J.B., Barends., D.M., (2011). Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ciprofloxacin Hydrochloride., J. Pharm. Sci.100, 1.
    • Pacher, P. Beckman, J. S. Liaudet., L. (2007). Nitric Oxide and Peroxynitrite in Health and Disease. Physiol Rev. 87, 315-424.
    • Palm, K., Luthman, K., Ros., J., Grasjo, J., Artursson., P., (1999). Effect of Molecular Charge on Intestinal Epithelial Drug Transport: pH-Dependent Transport of Cationic Drugs. JPET 291:435-443, 1999
    • Park, H., Kim, T., Bark. K., (2002). Physicochemical properties of quinolone antibiotics in various environments., Eur. J. Med. Chem. 37 443-460
    • Park, M. S. Leslie H. O., Benet, Z. (2011). Is Ciprofloxacin a Substrate of P-glycoprotein? Arch Drug Info. 4,1-9
    • Pappenheimer, J.R. and Reiss, K.Z. (1987). Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 100, 123-136.
    • Petris, M.J., (2004). The SLC31 (Ctr) copper transporter family, Pflugers Arch. 447, 752-755
    • Petrosyan, A.M. (2007). Vibrational spectra of L-histidine perchlorate and L-histidine Tetrafluoroborate. Vibrational Spectroscopy. 43, 284-289
    • Pellegata R.L., (1993). Furosamide salts, United states patent, 5,182,300
    • Pinto, M., Robine-Leon, S., Appay, M.-D., Kedinger, M., Triadou, N., Dussaulx, E., Lacroix, B., Simon-Assmann, P., Haffen, K., Fogh, J., Zweibaum, A., (1983). Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture. Biol. Cell 47: 323- 330.
    • Pistolis, G. , Andreopoulou, A. K. Malliaris, A. and Kallitsis., J. K. (2005). Direct Observation of Odd-Even Effect in Dilute Polymeric Solutions: A Time-Resolved Fluorescence Anisotropy Study., J. Phys. Chem. B. 109, 11538-11543
    • Poole, S.K., Poole, C.F., (2003). Separation methods for estimating octanol-water partition coefficients. J. Chromatogr. B. 797, 3-19.
    • Pratt, S., Chen, V., Perry, W.I., Starling, J.J., Danzig, A., (2006). Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur. J. Pharm. Sci. 27, 524-532.
    • Pochopin NL, Charman WN, Stella VY (1995). Amino acid derivatives of dapsone as water soluble prodrugs. Int J Pharm. 121, 157 - 167
    • Polli, J. W. Wring, S. A. Humphereys, J. E. Huang, L. Morgan, J. B. Webester, L. O. SerabjitSingh C., (2001). Rational Use of in Vitro P-glycoprotein Assays in Drug Discovery., The journal of pharmacology and experimental therapeutics. 299, 2
    • Quintanar-Guerrero, D., Allémann, E., Fessi, H., Doelker, E., (1997). Applications of the IonPair Concept to Hydrophilic Substances with Special Emphasis on Peptides., Pharm. Res. 14, (2), 119-127
    • Raj. S., Muthiah, P. T., Rychlewska, U., Warzajtis. B. (2003). Pseudo-polymorphism and crystal engineering: hydrogen-bonded supramolecular networks in trimethoprim m-chlorobenzoate and trimethoprim m- chlorobenzoate dehydrate. CrystEngComm. 5,9, 48-53
    • Ramaswamy, C.M., Varma, Y.B.G., Venkateswarlu, D., (1970). Compaction of mixtures of materials, Chem. Eng. J. 1 168-171.
    • Rasenack, N., Muller, B.W., (2002). Crystal Habit and Tableting Behaviour, Int. J. Pharm. 244, 45-57.
    • Ratain, M.J., Cohen, E.E., (2007). The value meal: how to save $1,700 per month or more on lapatinib, J. Clin. Oncol. 25, 3397-3398.
    • Rauchwerger, D.R., Firby, P.S., Hedley, D.W., Moore, M.J., (2000). Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity, Cancer Res. 60, 6075-6079
    • Rege, BD., Kao ,JP., Polli, JE., (2002). Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers., Eur. J. Pharm. Sci. 16, 237-246
    • Reizer, J., Michotey, V., Reizer, A. & Saier, M. H., (1994). Novel phosphotransferase system genes revealed by bacterial genome analysis : unique, putative fructose- and glucosidespeci®c systems. Protein Sci 3, 440- 450.
    • Riippi, M., Antikainen, O., Niskanen, T., Yliruusi. J., (1998). The effect of compression force on surface structure, crushing strength, friability and disintegration time of erythromycin acistrate tablets., Eur. J. Pharm. and Bio. 46, 339-345.
    • Robert, P. Igo, Jr. and John F. Ash., (1998). The Na+-Dependent Glutamate and Aspartate Transporter Supports Glutathione Maintenance and Survival of CHO-K1 Cells., Somatic Cell and Molecular Genetics. 24, 6, 341-352
    • Rohwedder, R., Bergan, T., Thorsteinsson, S.B. & Scholl, H. (1990). Transintestinal elimination of ciprofloxacin. Chemotherapy, 36, 77 - 84.
    • Roma˜nuk, C.B., Garro Linck, Y., Chattah, A.K., Monti, G.A., Cuffini, S.L., Garland, M.T., Baggio, R., Manzo, R.H., Olivera,. M.E., (2010). Crystallographic, thermal and spectroscopic characterization of a ciprofloxacin saccharinate polymorph. Int. J. Pharm. 391 197-202
    • Roma˜nuk, C.B., Garro Linck, Y., Chattah, A.K., Monti, G.A., Manzo, R.H., Olivera, M.E., (2009). Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones. J. Pharm. Sci. 98, 3788.
    • Romiti, N., Tramonti, G., Chieli., E., (2002). Influence of Different Chemicals on MDR-1 PGlycoprotein Expression and Activity in the HK-2 Proximal Tubular Cell Line., Toxicology and Applied Pharmacology 183, 83-91
    • Rubinstein, E., St Julien, L., Ramon, J., Dautrey, S., Farinotti, R., Huneau, J.F., Carbon, C. (1994). The intestinal elimination of ciprofloxacin in the rat. J. Infect. Dis. 169, 218 - 221.
    • Rubio-Aliaga I., Daniel H. (2002). Mammalian peptide transporters as targets for drug delivery. Trends Pharmacol Sci. 23, 434-440.
    • Ruhemann, S., J. (1911). Chem. Sot., 99,792, 1306-1486.
    • Ryckaert, J. P., Ciccotti, G., Berendsen, H. J., (1977). Numerical-integration of cartesian equations of motion of a system with constrains - molecular dynamics of n-alkanes. J Comput Phys. 23 ,3 , 327-341.
    • Ryshkewitch, E., (1953). Compression strength of porous sintered alumina and zirconia. J. Am. Cer. Soc. 36, 65-68.
    • Sadeek, S. A., El-Shwiniy, W. H., Zordok, W. A., El-Didamony, A. M., (2011). Spectroscopic, structure and antimicrobial activity of new Y(III) and Zr(IV) ciprofloxacin. Spectroc. Acta Pt. AMolec. Biomolec. Spectr. 78, 2, 854-867.
    • Sagui, C., Darden, T. A., (1999). In P3M and PME: a comparison of the two methods, Workshop on Treatment of Electrostatic Interactions in Computer Simulations of Condensed Media, Santa Fe, Nm, Jun 23-25; Pratt, L. R.; Hummer, G., Eds. Santa Fe, Nm, 104-113.
    • Sagui, C., Pedersen, L. G., Darden, T. A., (2004). Towards an accurate representation of electrostatics in classical force fields: Efficient implementation of multipolar interactions in biomolecular simulations. J Chem Phys. 120, 1, 73-87.
    • Saier,M.H., (2000). Families of transmembrane transporters selective for amino acids and their derivatives., Microbiology. 146, 1775-1795
    • Sahai, J., Gallicano, K., Oliveras, L., Khaliq, S., Hawley-Foss, N., Garber, G,. (1993). Cations in the didanosine tablet reduce ciprofloxacin bioavailability. Clin. Pharmacol. Ther. 53, 292-297.
    • Salama, N. Eddington, N. D. Fasano A. (2006). Tight junction modulation and its relationship to drug delivery ., Adv. Drug Deliv. Rev. 58, 15- 28
    • Sanna Siissalo, Laura Laine, Ari Tolonen, Ann M. Kaukonen, Moshe Finel , Jouni Hirvonen., (2010). Caco-2 cell monolayers as a tool to study simultaneous phase II metabolism and metabolite efflux of indomethacin, paracetamol and 1-naphthol. Int. J. Pharm. 383, 24-29
    • Sangekar, S.A., Sarli, M., Sheth, P. R, (1972). Effect of Moisture on Physical Characteristics of Tablets Prepared from Direct Compression Excipients, J. Pharm. Sci., 61, 939-944.
    • Sangster, J. (1989.) Octanol-Water Partition Coefficients of Simple Organic Compounds. J. Phys. Chem. 18, 3.
    • Santamarina-Fojo, S. Peterson, K. Knapper, C. Qiu, Y. et al., (2000). Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP binding cassette A promoter, Proc. Natl. Acad. Sci. U. S. A. 97, 7987-7992
    • Sam, A.P., Fokkens, J.G., (1997). Drug Delivery System: Adding Therapeutic and Economic Value to Pharmacotherapy. Part 2, Pharm. Tech. Eur. 9, 58-66.
    • Sastry, S.V., Nyshadham,J.R., Fix., J.A., (2000). Recent technological advances in oral drug delivery - a review. PSTT .3 ,4.
    • Schinkel, A.H., Mayer, U., Wagnaar, E., et al., (1997). Normal viability and altered phamacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad. Sci. U.S.A. 94, 4028-4033.
    • Schwartz, D. E., Vetter, W., and Englert, G. (1970). Trimethoprim metabolites in rat, dog and man: Qualitative and quantitative studies. Arzneimittelforschung. 20, 1867-1871.
    • Segawa, H., Fukasawa, Y., Miyamoto, K., Takeda, E., Endou, H., Kanai, Y., (1999). Identification and functional characterization of a na+-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274, 19745-19751
    • Sekiguchi, K., Obi, N. (1961). Studies on absorption of eutectic mixtures. I. A comparison of the behavior of eutectic mixtures of sulphathiazole and that of ordinary sulphathiazole in man. Chem. Pharm. Bull. 9, 866-872
    • Sekiguchi, K. and Obi, N. (1964). Studies on Absorption of Eutectic Mixture. Ii. Absorption of Fused Conglomerates of Chloramphenicol and Urea in Rabbits.
    • Chem. Pharm. Bull. 12, 134-144
    • Seelig, A., Gottschlich, R. and Devant, R.M. (1994). A method to determine the ability of drugs to diffuse through the blood-brain barrier. Proc. Natl. Acad. Sci. USA. 91, 68-72.
    • Serajuddin, A.T.M. (2007). Salt formation to improve drug solubility, Adv. Drug Deliv. Rev. 59, 603-616
    • Serajuddin, A.T.M., Mufson, D. (1985). pH-solubility profiles of organic bases and their hydrochloride salts, Pharm. Res. 2, 65-68.
    • Serajuddin, A.T.M., Jarowski, C.I. (1985). Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts I: phenazopyridine, J. Pharm. Sci. 74, 142-147.
    • Shannon., W. Culverhouse., R. Duncan., J. (2003). Analyzing microarray data using cluster analysis., Pharmacogenomics. 4,1, 41-51
    • Shastri, S., Mroszczak, E., Prichard, R.K., Parekh, P., Nguyen, T.H., Hennessey, D.R. Schlitz, R. (1980). Relationship among particle size distribution, dissolution profile, plasma values and anthelmintic efficacy of oxfendazole. Am. J. Vet. Res., 41 2095-2101.
    • Sheikh-Salem, M., Fell, J.T. (1981). Compaction characteristics of mixtures of materials with dissimilar compaction mechanisms, Int. J. Pharm. Tech. Prod. Mfr. 2, 19-22.
    • Shiau, Y.F., Fernandez, P., Jackson, M.J., Mcmonagle, S., (1985). Mechanisms maintaining a low-pH microclimate in the intestine. Am. J. Physiol. 248, G608-G617.
    • Shibata, Y., Fujii, M., Okada, H., Noda, S., Kondoh, M., Watanabe, Y., (2005). Evaluation of the Compaction Properties of a Solid Dispersion ofIndomethacin with Crospovidone by Tableting Process Analyzer. Chem Pharm Bull. 53, 7, 759-763.
    • Shin, H., Landowski C., Sun, D., Amidon, G., (2003). transporters in the GI tract in Drug Bioavailability/Estimation of Solubility, Permeability and Absorption, Waterbeemd H., Lennernas H., Artursson. P., eds. wiley-vch: Germany.
    • Shih, A.Y., Erb,H., Sun, X., Toda, S., Kalivas, P., Murphy T.H., (2006). Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation., The Journal of Neuroscience, 26, 41, 10514 -10523.
    • Shore, P.A., Brodie, B.B., Hogben, C.A.M., (1957). The gastric secretion f drugs: a pH partition hypothesis. J. Pharmacol. Exp. Ther. 119, 61-369.
    • Silverstein, R.M., Webster, F.X., (1998). Spectrometric Identification of Organic Compounds, 6th ed. Wiley: New York.
    • Simonelli, A.P. et al. (1969). Dissolution rates of high energy polyvinylpyrrolidone (PVP)- sulfathiazole coprecipitates. J. Pharm. Sci. 58, 538-549
    • Singh, B.N., (1999). Effects of food on clinical pharmacokinetics, Clin. Pharmacokinet. 37 213- 255.
    • Staniforth, J.N., (2007). Powder flow, in Aulton ME (eds), Pharmaceutics - the science of dosage form design. 3rd ed., Churchill Livingstone: London, UK.
    • Stahl, H., Wermuth, C.G. (Eds.) (2002). Handbook of Pharmaceutical Salts: Properties, Selection and Use. Wiley-VCH: Zurich.
    • Soergel, F., Naber, G., Jaedhe, U., Reiter, A., Seelmann, R. Sigl, G. (1989). Brief report: Gastrointestinal secretion of ciprofloxacin. Am. J. Med., 87 (suppl. 5A), 62-65.
    • Song, X.; Lorenzi,P.L.; Landowski, C.P.; Vig, B.S.; Hilfinger, J.M.; Amidon, G. (2004). Amino Acid Ester Prodrugs of the Anticancer Agent Gemcitabine: Synthesis, Bioconversion, Metabolic Bioevasion, and hPEPT1-Mediated Transport., Molecular Pharmaceutics. 2, 2, 157-167
    • Southern E, Mir K, Shchepinov M. (1999). Molecular interactions on microarrays. Nat Genet. 21, 5-9.
    • Socrates, G. Infrared Characteristic Group Frequencies, 2nd ed. Wiley: New York, 1994.
    • Soppelaa, I., Airaksinenb, S., Murtomaac, M., Tenhoc, M., Hataraa, J., Räikkönena, H., Yliruusia, J. Sandlerb, N., (2010). Investigation of the powder flow behaviour of binary mixtures of microcrystalline celluloses and paracetamol., J. Excipients and Food Chem. 1, 1.
    • Sun, C., Grant, J.W., (2001). Compaction Properties of L-Lysine Salts Pharm. Res. 18, 3
    • Sun, H., Seshadri, M. Lingard, S., Monaghan, W., Faoagali, J., Chan, E., McDonald, H., Houston, King, T., Peak, I., Wilson, J. C., Haywood, A., Spencer, B., Dunn P., Grant ., G. (2011). Antibacterial Activity of b-Cyclodextrin and 2-Hydroxypropyl- b-Cyclodextrin Trimethoprim Complexes., American Journal of Microbiology 2, 1, 1-8.
    • Susana, A., Breda, F., Jimenez-Kairuz, H., Manzo, E., (2009). Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives., Int. J. Pharm. 371, 106-113
    • Szabó-Révész, P., Göczõ. H., Pintye-Hódi K., Kása jr P., Erõs, I., Hasznos Nezdei, M. , Farkas, B., (2001). Development of spherical crystal agglomerates of an aspartic acid salt for direct tablet making., Powder Technology. 114, 118-124.
    • Tahvanainena, M., Rotkoa, T., Mäkiläb, E., Santosa, H.A., Nevesa, D., Laaksonen, T., Kallonenc, A. et al., (2012). Tablet preformulations of indomethacin-loaded mesoporous silicon Microparticles., Intr. J. Pharm. Sci 422, 125- 131
    • Taipalensuu, J., Rnblom, H., Lindberg, G., et al., (2001). Correlation of Gene Expression of Ten Drug Efflux Proteins of the ATP-Binding Cassette Transporter Family in Normal Human Jejunum and in Human Intestinal Epithelial Caco-2 Cell Monolayers., The Journal of Pharmacology and Experimental therapeutics., 299, 1.
    • Takanaga, H., Mackenzie, B., Peng, J., Hediger M. A. (2005). Characterization of a branchedchain amino-acid transporter SBAT1 (SLC6A15) that is expressed in human brain., Biochemical and Biophysical Research Communications. 337, 892-900
    • Takagi, M., Taki, Y., Sakane, T., Nadai, T., Sezaki, H., Oku, N., Yamashita, S., (1998). A new interpretation of salicylic acid transport across the lipid bilayer: implications of pH-
    • Tamai, I., Yabuuchi, H., Nezu, J., Sai, Y., Oku, A., Shimane, M., Tsuji, A. (1997). Cloning and Characterization of a Novel Human pH-dependent Organic Cation Transporter, OCTN1. FEBS Lett. 419, 107-111.
    • Tamai, I. et al. (1998). Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1. J. Pharm. Sci. 87, 1542-1546
    • Tan, W. Colombini., M., (2007). VDAC closure increases calcium ion flux., Biochimica et Biophysica Acta. 1768, 2510-2515
    • Tavelin, S., Milovic, V., Ocklind, G., Olsson, S., Artursson, P., (1999). A conditionally immortalized epithelial cell line for studies of intestinal drug transport. J. Pharm. Exp. Ther. 290, 1212-1221.
    • Thiel-Demby, V. E. Humphreys, J. E. St. John Williams, L. A. Ellens, H. M. Shah, N. Ayrton, and Joseph A. D. Polli., W. (2009). Biopharmaceutics Classification System: Validation and Learnings of an in Vitro Permeability Assay., Molecular pharmaceutics. 6, 1, 11-18.
    • Thwaites, D.T., McEwan, G.T.A., Hirst, B.H., Simmons, N.L., (1995). H+-coupled α- methylaminoisobutyric acid transport in human intestinal Caco-2 cells. Biochim. Biophys. Acta. 1234,111-118.
    • Tran, C.D.H., Timmins, P., Conway, B.R., Irwin, W.J., (2002). Investigation of the coordinated functional activities of Cytochrome P450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cells. J. Pharm. Sci. 91, 117-128.
    • Tsuji, A., Simanjuntak, M.T., Tamai, I., Terasaki, T., (1990). pH-Dependent intestinal transport of monocarboxylic acids: carrier-mediated and H(+)-cotransport mechanism versus pH partition hypothesis. J. Pharm. Sci. 79, 1123-1124.
    • Tsuji, A., Takanaga, H., Tamai, I., Terasaki, T., 1994. Transcellular transport of benzoic acid across Caco-2 cells by a pH-dependent and carrier-mediated transport mechanism. Pharm. Res. 11, 30-37.
    • Tsukita, S. Furuse, M. (1999). Occludin and claudins in tight junction strands: leading or supporting players, Trends Cell Biol. 9, 268- 273
    • Tong, P.; Zografi. G. (2001). A Study of Amorphous Molecular Dispersions of Indomethacin and Its Sodium Salt. J. Pharm. Sci, 90, 12.
    • Toukmaji, A., Sagui, C., Board, J., Darden, T., (2000). Efficient particle-mesh Ewald based approach to fixed and induced dipolar interactions. J Chem Phys. 113, 24, 10913-10927.
    • Tung H., Waterson S., Reynolds S.D., (1991). united states patent, 4,994, 604
    • Turel, I., Zivec, P., Pevec, A., Tempelaar, S., Psomas, G., (2008). Compounds of antibacterial agent ciprofloxacin and magnesium - Crystal structures and molecular modeling calculations. Eur. J. Inorg. Chem. 23, 3718-3727.
    • Uhl, G.R. Kitayama, S. Gregor, P. Nanthakumar, E. Persico, A. Shimada, S. (1992). Neurotransmitter transporter family cDNAs in a rat midbrain library: _orphan transporters_ suggest sizable structural variations, Brain Res. Mol. Brain Res. 16, 353-359.
    • Utsunomiya-Tate, N., Endou, H., Kanai, Y., (1997). Tissue specific variants of glutamate transporter GLT-1. FEBS Lett. 416, 312-316.
    • Upshall, D.G., Gouldstone, S.J., Macey, N., Maidment, M.P., West, S.J. and Yeadon, M., (1990). Conversion of a peptidoaminobenzophenone prodrug to diazepam in vitro. Enzyme isolation and characterisation. J. Biopharm. Sci. 1, 111-126.
    • Van Drooge, D.J. et al. (2006). Characterization of the molecular distribution of drugs in glassy solid dispersions at the nano-meter scale, using differential scanning calorimetry and gravimetric water vapour sorption techniques. Int. J. Pharm. 310, 220-229
    • Van, T., Klooster, G. A., Kolker, H. J., Woutersen-Van Nijnanten, F. M., Noordhoek, J., and Van Miert, A. S. (1992). Determination of trimethoprim and its oxidative metabolites in cell culture media and microsomal incubation mixtures by high performance liquid chromatography. J. Chromatogr. 579, 354-360.
    • Van Veen, B. Maarschalk, K., Bolhuis, G.K., Zuurman, K., Frijlink, H.W., (2000). Tensile strength of tablets containing two materials with a different compaction behaviour, Int. J. Pharm. 203, 71-79.
    • Van Veen, B., Maarschalk, K., Bolhuis, G.K. Frijlink, H.W., (2004). Predicting mechanical properties of compacts containing two components, Powder Technol. 139 156-164
    • Vasconcelos, T., Sarmento, B., Costa., P., (2007), Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs., Drug Discovery Today , 12, 23-24.
    • Veen, B.V., Maarschalk, V., Bolhuis, G.K., Zuurman, K., Frijlink. H.W., (2000). Tensile strength of tablets containing two materials with a different compaction behaviour., Int. J. Pharm. 203, 71-79.
    • Vromans, H., Lerk, C.F., (1988). Densification properties and compactibility of mixtures of pharmaceutical excipients with and without magnesium stearate. Int. J. Pharm. 46, 183-192.
    • Volk, E.L., Schneider, E., (2003), Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter, Cancer Res. 63, 5538-5543
    • Wacher, V.J et al., (1998). Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J. Pharm. Sci., 87, 1322- 1330.
    • Walter, E., Kissel, T., Amidon, G.L. , (1996). The intestinal peptide carrier: a potential system for small peptide derived drugs, Adv. Drug Deliv. Rev. 20, 33 58.
    • Wang, J. M., Wolf, R. M., Caldwell, J. W., Kollman, P. A., Case, D. A., 2005. Development and testing of a general amber force field. Journal of Computational Chemistry. 26, 1, 114-114.
    • Washington, N., Washington, C. and Wilson, C. (2001). Physiological Pharmaceutics: Barriers to Drug Absorption, 2nd Ed. Taylor & Francis: London, UK.
    • Watari, N., Funaki, T., Aizawa, K. and Kaneniwa, N. (1983). Nonlinear assessment of nitrofurantoin bioavailability in rabbits. J. Pharmacokinet. Biopharm., 11, 529-545.
    • Weller, S., Blum, M.R., Doucette, M., Burnette, T., Cederberg, D.M., Miranda, P., Smiley, M.L., (1993). pharmacokinetics of acyclovir prodrug valaciclovir after escalating single and multiple dose administration to normal volunteers. Clin. Pharmacol. Ther. 54, 595-605
    • Wetterich, U., Spahn-Langguth, H., Mutschler, E., Terhaag, B., Rösch, W., Langguth, P., (1996 ). Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo., Pharm Res. 13, 4, 514- 522.
    • Wetzstein, H., Stadler, M., Dalhoff, A., Karl, W., (1999). Degradation of Ciprofloxacin by Basidiomycetes and Identification of Metabolites Generated by the Brown Rot Fungus Gloeophyllum striatum. Applied and environmental microbiology. 65,4, 1556-1563
    • Widmaier, E. P., Raff, H. and Strang, K. T. (2011). Vander's Human Physiology: The Mechanisms of Body Function, 12th Ed. McGraw-Hill: New York.
    • Worth, A.P., Balls, M., ed. (2002). Alternative (non-animal) Methods for Chemicals Testing: Current Status and Future Prospects. ATLA. 30, 1, 125
    • Wu, X., George, R. L., Huang, W., Wang, H., Conway, S. J., Leibach, F. H., Ganapathy, V.( 2000). Structural and Functional Characteristics and Tissue Distribution Pattern of Rat OCTN1, an Organic Cation Transporter, Cloned from Placenta. Biochim. Biophys. Acta. 1466, 315-327.
    • Wu, C., Benet, L.Z., (2005). Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System., Pharm Res. 22, 1.
    • Wu, C., Best, S.M., Benthamb, A.C., Hancock, B.C., Bonfield. W. (2005). A simple predictive model for the tensile strength of binary tablets. Eur J Pharm Sci. 25, 331-336.
    • Wu, X. W., Brooks, B. R., (2003). Self-guided Langevin dynamics simulation method. Chemical Physics Letters. 381 ,3, 512-518.
    • Zakelj, S., Sturm K., Krist., A., (2006). Ciprofloxacin permeability and its active secretion through rat small intestine in vitro., Int. J. Pharm. 313, 175-180
    • Zeller, V., Janoir, C., Kitzis, M., Gutmann, L., Moreau., N.J., (1997). Active Efflux as a Mechanism of Resistance to Ciprofloxacin in Streptococcus pneumoniae., Antimicrobial agents and chemotherapy. 41, 9.
    • Zhao, Y.H., Le, J., Abraham, M.H., Hersey, A., Eddershaw, P.J., Luscombe, C.N., Boutina, D., Beck, G., Sherborne, B., Cooper, I., Platts, J.A, (2000). Evaluation of Human Intestinal
    • Yamashita, S., Furubayashi, T., Kataoka, M., Sakane, T., Sezaki, H., Tokuda, H., 2000. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur. J. Pharm. Sci. 10, 195-204.
    • Ye , D. Meurs, I. Ohigashi, M. Calpe-Berdiel, L. Habets, K. Zhao Y., et al., (2010). Macrophage ABCA5 deficiency influences cellular cholesterol efflux and increases susceptibility to atherosclerosis in female LDLr knockout mice., Biochemical and Biophysical Research Communications. 395, 387-394
    • Yee, S., (1997). In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man - fact or myth. Pharm. Res. 14, 763-766.
    • Young, R.C., Mitchell, R.C., Brown, T.H., Ganellin, C.R., Griffiths, R., Jones, M., Rana, K.K., Saunders, D., Smith, I.R., Sore, N.E. and Wilks, T.J. (1988). Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H receptor histamine antagonists. J. Med. Chem. 31, 656-671.
    • Zerangue, N., Kavanaugh, M.P., (1996). ASCT-1 is a neutral amino acid exchanger with chloride channel activity. J. Biol. Chem. 271, 27991- 27994.
    • (um500
    • ea400
    • ka300
    • ep200
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article