Kin Y Tam

University of Macau, Macao, Macau, Macao

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Publications (30)107.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Binding affinities of fluconazole and its analogue 2-(2,4-dichlorophenyl)-1,3-di(1H-1,2,4-triazol-yl)-2-propanol (DTP) to human serum albumin (HSA) were investigated under approximately human physiological conditions. The obtained result indicated that HSA could generate fluorescent quenching by fluconazole and DTP because of the formation of non-fluorescent ground-state complexes. Binding parameters calculated from the Stern-Volmer and the Scatchard equations showed that fluconazole and DTP bind to HSA with binding affinities of the order 10(4)L/mol. The thermodynamic parameters revealed that the binding was characterized by negative enthalpy and positive entropy changes, suggesting that the binding reaction was exothermic. Hydrogen bonds and hydrophobic interaction were found to be the predominant intermolecular forces stabilizing the drug-protein. The effect of metal ions on the binding constants of fluconazole-HSA complex suggested that the presence of Mg(2+) and Zn(2+) ions could decrease the free drug level and extend the half-life in the systematic circulation. Docking experiments revealed that fluconazole and DTP binds in HSA mainly by hydrophobic interaction with the possibility of hydrogen bonds formation between the drugs and the residues Arg 222, Lys 199 and Lys 195 in HSA.
    Bioorganic & Medicinal Chemistry Letters. 09/2014;
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    ABSTRACT: The purpose of this study is to predict human jejunal permeability (Peff) and fraction absorbed in human (%Fa) for a group of antibacterial fluoroquinolones (FQs), by using a biophysical model based on measured Caco-2 permeability. The predicted Peff (in 10-4cm·s-1 units) ranged from 0.7 (norfloxacin) to 4.5 (pefloxacin). The calculated %Fa for norfloxacin = 51% (lit. 35%) and for ciprofloxacin = 76% (lit. 81%). Most of the FQs showed calculated %Fa>90%, and are expected to be well-absorbed. Estimates of Peff can be predicted by the biophysical model. From these values, the human absorption may be calculated. Where absorption comparisons were possible, the agreement was acceptably good.
    Bio-medical materials and engineering 01/2014; 24(6):3849-54. · 1.09 Impact Factor
  • Wen Zhang, Chenyin Wang, Kin Y Tam
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    ABSTRACT: The objective of this study is to evaluate whether the accumulation model developed by Zarfl et al. (2008) could be used to predict the minimal inhibitory concentration (MIC) of a group of antibacterial fluoroquinolones (FQs) for Escherichia coli (E. coli). Our model, which is based on the "Fick-Nernst-Planck" equation and the permeability of the neutral and charged species as well as the physicochemical parameters of the FQs, could predict 1/MIC90 using a linear function. It is envisaged that in the drug development projects of new FQs, the accumulation model described in this study could be utilized as an effective tool to enable early assessment of MIC value using physiochemical parameters.
    Bio-medical materials and engineering 01/2014; 24(6):3745-51. · 1.09 Impact Factor
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    ABSTRACT: A polarization study carried out on a thin supported liquid membrane separating two aqueous compartments is presented. Transfer of both the ionized and uncharged form of an organic tracer dye, rhodamine B ([9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride), across supported liquid membranes composed of one of 1-octanol (octan-1-ol), 1,9-decadiene (deca-1,9-diene), 1,2-dichlorobenzene or nitrophenyl octyl ether (1-(2-nitrophenoxy)octane), was studied using cyclic voltammetry and UV-vis absorption spectrophotometry. Concentration analysis indicates that the high membrane concentration of rhodamine B determines the ionic transfer observed via voltammetry, which is consistent with the low aqueous ionic concentration and large membrane/aqueous distribution of the molecule. The observed double-transfer voltammogram, although it has been largely neglected in previous literature, is a logical consequence of the presence of two liquid-liquid interfaces and is rationalised in terms of ion transfer across the two interfaces on either side of the membrane and supported by voltammograms obtained for a series of ions of varied lipophilicity. The bipolar nature of the voltammetric response offers an effective way of mass transport control via changing polarity of the applied voltage and finds immediate use in extraction, purification and separation applications.
    Analytical Chemistry 12/2013; · 5.82 Impact Factor
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    ABSTRACT: ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonyl-morpholino-pyrimidines which show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in-vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in-vivo.
    Journal of Medicinal Chemistry 02/2013; · 5.61 Impact Factor
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    ABSTRACT: The purpose of this study is to develop a droplet-based microfluidic device capable of monitoring drug precipitation upon a shift from gastric pH (pH 1.5) to intestinal pH (pH 6.5-7.0). The extent of precipitation occurring in droplets over time was measured using a novel on-chip laser scattering technique specifically developed for this study. The precipitation of ketoconazole, a poorly water-soluble basic drug, was investigated under different concentrations and pH values. It has been shown that the drug precipitates rapidly under supersaturation. Two water-soluble aqueous polymers, namely, polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) have been evaluated as precipitation inhibitors. HPMC was shown to be the most potent precipitation inhibitor. It is envisaged that the microfluidic pH-shift method developed in this study would form a proof-of-concept study, towards the development of a high throughput method for screening pharmaceutical excipients/precipitation inhibitors.
    The Analyst 01/2013; 138:339-345. · 4.23 Impact Factor
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    ABSTRACT: The purposes of this study are to evaluate if the PAMPA (Parallel Artificial Membrane Permeability Assay) permeability and the true partition coefficient could be useful for predicting AUC and MIC data of a group of antibacterial fluoroquinolones (FQs). The protonation macro- and microconstants, the n-octanol/water partition coefficients at isoelectric pHs, and the PAMPA permeability of 11 selected FQs were determined, and used to calculate the true partition coefficient, the interactivity parameter between the acidic and basic group, and the apparent intrinsic permeability. It has been shown that the apparent intrinsic permeability correlates well with the AUC in human, whereas the true partition coefficient and the interactivity parameter correlate with 1/MIC values on two Gram-positive bacteria, namely Streptococcus pneumonia and Staphylococcus aureus (methicillin-susceptible). The AUC/MIC ratios predicted from these correlations have shown to be in good agreement with the literature values. It is envisaged that the models described in this study could be useful in the development of new FQs by enabling an early prediction of AUC/MIC ratios based on physicochemical properties.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2012; 47(1):21-7. · 2.61 Impact Factor
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    ABSTRACT: The preparation and application of a simple silver/silver sulfate reference electrode for an aqueous solution, which can be used as an alternative in chloride-free systems, is reported. The electrodes are prepared by galvanostatic oxidation of silver wire in sulfate solution: the potential stability with time is measured as a function of the current density and overall charge used in oxidation. The electrode potential is also measured in a wide concentration range of sulfate and chloride solutions and an explanation of the observed stability is presented. The range of optimal conditions, crucial for the correct electrode operation, is discussed.
    Analytical methods 05/2012; 4(5):1207-1211. · 1.86 Impact Factor
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    ABSTRACT: An analytical technique for the detection of permeation of a fully ionized analyte across a lipophilic membrane is reported. The system, which is comprised of two aqueous compartments (donor and acceptor) separated by a supported liquid membrane, is based on the parallel artificial membrane permeation assay (PAMPA), widely used in the drug discovery process to estimate permeability in vivo. The in situ spectroelectrochemical method developed here employs mechanical stirring of the solution phases on either side of the membrane, external polarization of the membrane, and in situ detection of the analyte via UV-vis spectrophotometry. The flux of the crystal violet cation across the membrane is simultaneously measured via UV-vis spectrophotometry and voltammetry/chronoamperometry as a function of applied potential. The relative contribution of two permeation modes, i.e., that due to naked ions and ion-pairs, is thereby quantified. The open circuit potential difference between the two aqueous compartments and the cyclic voltammetric response are also recorded as a function of time and compared with the predicted values.
    Analytical Chemistry 03/2012; 84(5):2541-7. · 5.82 Impact Factor
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    ABSTRACT: Chemoembolization has been used in the field of interventional oncology. Although practiced widely, it has only recently been demonstrated that the use of transarterial chemoembolization (TACE) provides a survival benefit based on randomized controlled trials. TACE combines the effect of targeted chemotherapy with the effect of ischemic necrosis induced by arterial embolization. Most of the TACE procedures have been based on iodized oil utilizing its microembolic and drug-carrying characteristics. Recently, there have been efforts to improve the delivery of chemotherapeutic agents to a tumor, which leads to the development of drug-eluting particles. In this review, we will describe the properties and efficacy of some chemoembolization agents which are commercially available and/or currently under clinical investigations. The potential and future of this new form of transcatheter arterial therapy for liver cancer will be discussed.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 09/2011; 44(1-2):1-10. · 2.61 Impact Factor
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    ABSTRACT: The purpose of this study was to develop an in vitro permeation model that will predict the fraction of drugs absorbed in humans. A rotating-diffusion cell with two aqueous compartments, separated by a lipid-impregnated artificial membrane, was used to determine the permeability of drugs under conditions of controlled hydrodynamics. The measured effective permeability coefficient was modified to include the paracellular transport derived from a previously reported colorectal adenocarcinoma epithelial cell line (Caco-2) permeability study and the effects of unstirred water layer anticipated in vivo. Permeability data were collected for 31 different marketed drugs with known absolute oral bioavailability and human hepatic clearance data. Literature bioavailability values were corrected for the first pass hepatic clearance thus obtaining the fraction absorbed from intestinal lumen (fraction absorbed), F(a), while assuming that the fraction escaping intestinal extraction, F(g), was approximately ~1. Permeability obtained under conditions of controlled hydrodynamics was compared with the permeability measured under unstirred conditions. It is shown that the optimized effective permeability correlates with the fraction absorbed. In contrast, permeability data obtained under unstirred conditions does not show a good correlation. The in vitro permeation model developed in this study predicts the fraction absorbed of the selected drugs in humans within experimental uncertainty. It has been demonstrated that the correlation with the fraction absorbed is greatly improved using the permeability data obtained under controlled hydrodynamics with paracellular transport included in the model.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 08/2011; 44(3):299-309. · 2.61 Impact Factor
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    ABSTRACT: The displacement of probes that bind selectively to subdomains IIA or IIIA on human serum albumin (HSA) by competing compounds has been followed using fluorescence spectroscopy, and has therefore been used to assign a primary binding site for these compounds in the presence and absence of fatty acids. The crystal structures have also been solved for three compounds: a matched pair of carboxylic acids whose binding strength to HSA unexpectedly decreased as the lipophilicity increased; and a highly bound sulphonamide that appeared not to displace the probes in the displacement assay. The crystallography results support the findings from the fluorescence displacement assay. The results indicate that drug binding to subdomain IB might also be important location for certain compounds.
    Bioorganic & medicinal chemistry 11/2010; 18(21):7486-96. · 2.82 Impact Factor
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    ABSTRACT: To investigate the permeation of two ionisable drug molecules, warfarin and verapamil, across artificial membranes. For the first time since the introduction of the parallel artificial membrane permeation assay (PAMPA) in 1998, in situ permeation-time profiles of drug molecules are studied. The method employs a rotating-diffusion cell where the donor and acceptor compartments are separated by a lipid-impregnated artificial membrane. The permeation of the solute is investigated under well-defined hydrodynamic conditions with control over the unstirred water layer. The flux of the permeating molecule is analysed in situ using UV spectrophotometry. In situ permeation-time profiles are obtained under hydrodynamic control and used to determine permeability coefficients. An advanced analytical transport model is derived to account for the membrane retention, two-way flux and pH gradient between the two compartments. Moreover, a numerical permeation model was developed to rationalise the time-dependent permeation profiles. The membrane permeability, intrinsic permeability and unstirred water permeability coefficients of two drug molecules are obtained from two independent methods, hydrodynamic extrapolation and pH profiling, and the results are compared. Both warfarin and verapamil exhibit high permeability values, which is consistent with the high fraction absorbed in human. Our results demonstrate that a considerable lag-time, varying with the solute lipophilicity and stirring rate, exists in membrane permeation and leads to incorrect compound ranking if it is not treated properly. Comparison of the permeability data as a function of pH and stirring rate suggests that some transport of the ionized molecules occurs, most likely via ion-pairing.
    Pharmaceutical Research 05/2010; 27(8):1644-58. · 4.74 Impact Factor
  • Alex Avdeef, Kin Y Tam
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    ABSTRACT: The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.
    Journal of Medicinal Chemistry 04/2010; 53(9):3566-84. · 5.61 Impact Factor
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    ABSTRACT: The permeability characteristics of 33 amphoteric drugs (about 64% zwitterions at physiological pH) were studied using the parallel artificial membrane permeability assay (PAMPA) at pH 6.5. The PAMPA data were modified to include the paracellular permeability component found in cellular monolayers based on a newly generalized version of a popular model devised for Caco-2 cells. These "in combo" PAMPA data were used to predict the human absolute bioavailability of the ampholytes. The analysis produced a good fit, with only five outliers whose transport properties, could be rationalized by (a) nonpassive permeability processes, (b) metabolic instability, and (c) the possible sensitivity to microclimate pH effects in the case of acidic ampholytes. With the exception of two compounds, all of the ampholytes with bioavailability <50% were predominantly transported by the paracellular route, surprisingly with several of the compounds having molecular weights exceeding 350 Da.
    Journal of Medicinal Chemistry 11/2009; 53(1):392-401. · 5.61 Impact Factor
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    ABSTRACT: The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.
    Bioorganic & medicinal chemistry letters 01/2009; 18(24):6369-73. · 2.65 Impact Factor
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    ABSTRACT: Colloid stable magnetic iron oxide nanoparticles, which undergo reversible precipitation from aqueous solution with external magnetic flux, can have many potential applications. However, the lack of generic homogeneous anchoring sites on a magnetic nanoparticle surface for binding of chemical/biochemical species under a wide range of conditions is one key problem. It is shown that a small size iron oxide nanoparticle encapsulated in a thin silica shell can offer specific sites to bind protein molecules via surface silanol groups electrostatically at pH 7.4 without severe denaturing of the bulky protein structure. As a result, we show that a high loading of bovine serum albumin (BSA) of 85 mg/g can be anchored on the silica-encapsulated iron oxide. FTIR, circular dichroism, and binding constant (using site I and site II drugs) measurements show only a small degree of conformational alteration upon immobilization. A partial unfolding of secondary structures on the external sheath of the protein due to competitive hydrogen bonding interactions of functional groups such as −CO and −NH with surface acidic hydroxyl groups is shown to take place despite the use of buffered pH 7.4 solution. In contrast to the blockage of drug binding sites reported in the case of anchored BSA on extended silica surface, our results clearly show that the internal hydrophobic sites I and II of the immobilized BSA on this silica-based magnetic nanoparticle remain intact for drugs binding at a high degree.
    Journal of Physical Chemistry C - J PHYS CHEM C. 12/2008; 113(2).
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    ABSTRACT: The development and application of a high throughput aqueous solubility assay is reported. Measurements for up to 637 compounds can be made in a fully automated experiment. Results from this assay were used to quantify risk of unacceptable solubility as a function of lipophilicity for neutral fragment-like compounds. Assessment of risk of unacceptable solubility was combined with experimental solubility measurement to select compounds for inclusion in a fragment-screening library.
    Bioorganic & medicinal chemistry 08/2008; 16(13):6611-6. · 2.82 Impact Factor
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    ABSTRACT: An in situ analytical approach to the measurement of supported liquid membrane permeability is reported. The method consists of a spectrophotometric method to measure transport through a membrane-supported lipid solution, using a rotating-diffusion cell configuration to overcome limits arising from transport through the aqueous solution boundary layer in stationary systems. Rotation frequencies are almost two orders of magnitude higher than those employed previously for rotating-diffusion studies of membrane transport. The method is illustrated with the transport of warfarin [1-(4'-hydroxy-3'-coumarinyl)-1-phenyl-3-butanone]. The use of the rotating-diffusion approach permits accurate calculation of the aqueous phase boundary layer thickness, which has hitherto been treated as an adjustable parameter in studies of membrane permeability. Further, it is shown that the analyte diffusion coefficient can be determined readily using liquid-liquid electrochemistry.
    The Analyst 06/2008; 133(5):655-9. · 4.23 Impact Factor
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    ABSTRACT: Recent development in assembling nanoparticles as building blocks into macroscopic functional structures or devices to harness the size-dependent properties of individual particles is an exciting new direction. Here, it is demonstrated that well-dispersed silica- encapsulated superparamagnetic FePt nanoparticles in solution can be assembled into high-quality, needle- or rod-shaped solid-state supercrystals by applying inhomogeneous external magnetic field together with controlled evaporation. By use of an aggregation model based on the population balance equation technique, this charactersitic morphology of the magnetic asembled crystals can be successfully derived.
    Journal of Physical Chemistry C - J PHYS CHEM C. 04/2008; 112(20).

Publication Stats

192 Citations
107.76 Total Impact Points

Institutions

  • 2013–2014
    • University of Macau
      • Faculty of Health Sciences
      Macao, Macau, Macao
  • 2008–2013
    • The University of Manchester
      • • School of Chemical Engineering and Analytical Science
      • • School of Chemistry
      Manchester, ENG, United Kingdom
  • 2000–2012
    • Semmelweis University
      • Department of Pharmaceutical Chemistry
      Budapest, Budapest fovaros, Hungary
  • 2010
    • Pion Inc.
      Billerica, Massachusetts, United States
  • 2005–2007
    • University of Reading
      • Department of Chemistry
      Reading, ENG, United Kingdom