The Experts below are selected from a list of 22530 Experts worldwide ranked by ideXlab platform
Phil Jupp - One of the best experts on this subject based on the ideXlab platform.
-
combined application of parallel artificial membrane permeability assay and caco 2 permeability assays in drug discovery
Journal of Pharmaceutical Sciences, 2004Co-Authors: Edward H. Kerns, Susan Petusky, Li Di, Michele Farris, Phil JuppAbstract:Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R2 = 0.76–0.92), indicating the predominance of Passive Diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced Passive Diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased Passive Diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess Passive Diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1440–1453, 2004
-
combined application of parallel artificial membrane permeability assay and caco 2 permeability assays in drug discovery
Journal of Pharmaceutical Sciences, 2004Co-Authors: Edward H. Kerns, Susan Petusky, Michele Farris, Rob Ley, Phil JuppAbstract:Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R(2) = 0.76-0.92), indicating the predominance of Passive Diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced Passive Diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased Passive Diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess Passive Diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms.
Edward H. Kerns - One of the best experts on this subject based on the ideXlab platform.
-
evidence based approach to assess Passive Diffusion and carrier mediated drug transport
Drug Discovery Today, 2012Co-Authors: Per Artursson, Manfred Kansy, Gerhard F. Ecker, Bernard Faller, Holger Fischer, Alex Avdeef, Edward H. Kerns, Brian J Houston, Stefaniedorothea Kramer, Hans LennernasAbstract:Evidence supporting the action of Passive Diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to Passive Diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.
-
combined application of parallel artificial membrane permeability assay and caco 2 permeability assays in drug discovery
Journal of Pharmaceutical Sciences, 2004Co-Authors: Edward H. Kerns, Susan Petusky, Li Di, Michele Farris, Phil JuppAbstract:Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R2 = 0.76–0.92), indicating the predominance of Passive Diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced Passive Diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased Passive Diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess Passive Diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1440–1453, 2004
-
combined application of parallel artificial membrane permeability assay and caco 2 permeability assays in drug discovery
Journal of Pharmaceutical Sciences, 2004Co-Authors: Edward H. Kerns, Susan Petusky, Michele Farris, Rob Ley, Phil JuppAbstract:Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R(2) = 0.76-0.92), indicating the predominance of Passive Diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced Passive Diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased Passive Diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess Passive Diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms.
J N Cape - One of the best experts on this subject based on the ideXlab platform.
-
the use of Passive Diffusion tubes for measuring concentrations of nitrogen dioxide in air
Critical Reviews in Analytical Chemistry, 2009Co-Authors: J N CapeAbstract:Passive Diffusion tubes have been widely used in Europe for spatial and temporal measurement of NO2 concentrations. The method is cheap, simple, and provides concentration data in most circumstances that are sufficiently accurate for assessing exposure and compliance with air quality criteria. Tube-type Diffusion samplers are prone to several sources of uncertainty, arising from the materials of construction, the absorbent used, the methods of preparation, the details of their deployment (including the exposure time) and the analytical methods used to establish the concentration of nitrite ion absorbed. This review considers the major sources of uncertainty, and reports on the many experiments aimed at identifying and minimizing uncertainties, including modifications to the simple open tube devices that were originally developed in the 1970s.
-
overestimation of urban nitrogen dioxide by Passive Diffusion tubes a comparative exposure and model study
Atmospheric Environment, 1999Co-Authors: Mathew R Heal, M A Odonoghue, J N CapeAbstract:Abstract A detailed comparative trial of Passive Diffusion tubes (PDT) for measurement of NO 2 in urban air has been undertaken in Edinburgh, UK. Acrylic, foil-wrapped and quartz tubes were exposed in parallel for 1-week and 4-week periods at three urban sites equipped with continuous analysers for NO, NO x and O 3 . Standard acrylic PDTs significantly overestimated NO 2 concentrations relative to chemiluminescence analysers, by an average of 27% over all sites for 1-week exposures. No significant difference was observed between standard and foil-wrapped acrylic tubes (both UV blocking). The mean ratio between quartz (UV transmitting) tubes and chemiluminescence analysers was 1.06. Quartz PDT data suggest a tendency for in situ photolysis to offset (but in a non-quantifiable way) the effect of chemical overestimation. The 4-week exposures yielded systematically lower NO 2 concentration than average NO 2 from four sequential 1-week exposures over the same period. The reduction in the apparent NO 2 sampling rate with time mostlikely arises from in situ photolysis of trapped NO 2 . Hourly NO 2 , NO and O 3 data for 20 1-week exposures were used as input to a numerical model of Diffusion tube operation incorporating chemical reaction between co-diffusing NO and O 3 within the tube. The mean calculated overestimation of 22% for NO 2 from the PDT model simulations is close to the average difference between acrylic PDT and analyser NO 2 concentrations (24% for the same exposure periods), showing that within-tube chemistry can account for observed discrepancies in NO 2 measurement between the two techniques. Overestimation by PDT generally increased as average NO 2 /NO x ratios decreased. Accurate quantitative correction of PDT measurements is not possible. Nevertheless, PDT NO 2 concentrations were correlated with both analyser NO 2 and NO x suggesting that acrylic PDTs retain a qualitative measure of NO 2 and NO x variation at a particular urban location.
-
a numerical evaluation of chemical interferences in the measurement of ambient nitrogen dioxide by Passive Diffusion samplers
Atmospheric Environment, 1997Co-Authors: Mathew R Heal, J N CapeAbstract:Abstract Passive Diffusion samplers containing tri-ethanolamine (TEA) as adsorbent are widely deployed for measuring NO2 concentrations in urban and rural air. In this study, a one-dimensional model of the sampler incorporating diffusive transport and chemical reaction has shown that NO2 concentrations are systematically overestimated as a result of chemical reactions in the tube, dominated by the reaction of NO with O3 to give NO2. The contribution of PAN and other potential interferents is shown to be small for British conditions. The extent of overestimation depends on the instantaneous [ NO ] [ NO 2 ] ratio and on the relative concentrations of NO and O3. In rural air, where [NO] The systematic error of within-tube chemistry is independent of, and acts in the same direction as, the possible overestimation caused by an effective shortening of Diffusion path length at high wind speeds and may be one explanation for Diffusion sampler overestimations previously attributed to wind effects. There appears to be no simple method for retrospectively correcting NO2 measurement data obtained using Diffusion tubes since the overestimate is not simply related to the average [ NO ] [ NO 2 ] nor [ NO ] [ O 3 ] ratios, but reflects the dynamical behaviour throughout the sampling period. Although Passive Diffusion samplers may give reliable concentration data for NOx in rural air, they cannot be used with confidence in polluted urban air to estimate NO2 concentrations.
Mathew R Heal - One of the best experts on this subject based on the ideXlab platform.
-
biases in the measurement of ambient nitrogen dioxide no2 by palmes Passive Diffusion tube a review of current understanding
Atmosphere, 2019Co-Authors: Mathew R Heal, Duncan P H Laxen, Ben MarnerAbstract:Palmes-type Passive Diffusion tubes (PDTs) are widely used to measure levels of nitrogen dioxide (NO2) in air quality studies. Molecules of NO2 diffuse down the concentration gradient established in the tube by their reactive conversion into nitrite (NO2−) with triethanolamine (TEA) absorbent at the inner end. The relatively low uptake rate for the tube geometry means that exposure-averaged NO2 concentration can be calculated from first principles using the Diffusion coefficient, D, for NO2 in air. This review provides a critical assessment of the current understanding of sources and extent of potential bias in NO2 PDT measurements in each of the following methodological stages: preparation of the absorbent; quantification of the absorbed NO2−; deployment in the field; calculation of the exposure-average NO2 concentration from the absorbed NO2−; and assessment of PDT bias through comparison against a chemiluminescence NO2 analyser. The review has revealed strong evidence that PDT measurement of NO2 can be subject to bias from a number of sources. The most significant positive biases are ambient wind flow at the entrance of the tube potentially leading to bias of tens of percent, and within-tube chemical reaction between NO and O3 causing bias up to ~25% at urban background locations, but much less at roadside and rural locations. Sources of potentially significant negative bias are associated with deployment times of several weeks in warm and sunny conditions, and deployments in atmospheres with relative humidities <~75% which causes incomplete conversion of NO2 to NO2−. Evidence suggests that biases (positive or negative) can be introduced by individual laboratories in the PDT preparation and NO2− quantification steps. It is insufficiently acknowledged that the value of D is not accurately known—some controlled chamber experiments can be interpreted as indicating that the value of D currently used is too low, giving rise to a positive bias in PDT-derived NO2 concentration. More than one bias may be present in a given PDT deployment, and because the biases act independently the net effect on PDT NO2 determination is the linear sum of individual biases acting on that deployment. The effect of net bias can be reduced by application of a local “bias adjustment” factor derived from co-locations of PDTs with a chemiluminescence analyser. When this is carried out, the PDT is suitable as an indicative measure of NO2 for air quality assessments. However, it must be recognised that individual PDT deployments may be subject to unknown variation in the bias adjustment factor for that deployment.
-
influence of wind speed on short duration no2 measurements using palmes and ogawa Passive Diffusion samplers
Atmospheric Environment, 2017Co-Authors: Nicola Masey, Mathew R Heal, Jonathan Gillespie, Scott Hamilton, Iain J BeverlandAbstract:We assessed the precision and accuracy of nitrogen dioxide (NO2) concentrations over 2-day, 3-day and 7-day exposure periods measured with the following types of Passive Diffusion samplers: standard (open) Palmes tubes; standard Ogawa samplers with commercially-prepared Ogawa absorbent pads (Ogawa[S]); and modified Ogawa samplers with absorbent-impregnated stainless steel meshes normally used in Palmes tubes (Ogawa[P]). We deployed these Passive samplers close to the inlet of a chemiluminescence NO2 analyser at an urban background site in Glasgow, UK over 32 discrete measurement periods. Duplicate relative standard deviation was < 7% for all Passive samplers. The Ogawa[P], Ogawa[S] and Palmes samplers explained 93%, 87% and 58% of temporal variation in analyser concentrations respectively. Uptake rates for Palmes and Ogawa[S] samplers were positively and linearly associated with wind-speed (P < 0.01 and P < 0.05 respectively). Computation of adjusted uptake rates using average wind-speed observed during each sampling period increased the variation in analyser concentrations explained by Palmes and Ogawa[S] estimates to 90% and 92% respectively, suggesting that measurements can be corrected for shortening of Diffusion path lengths due to wind-speed to improve the accuracy of estimates of short-term NO2 exposure. Monitoring situations where it is difficult to reliably estimate wind-speed variations, e.g. across multiple sites with different unknown exposures to local winds, and personal exposure monitoring, are likely to benefit from protection of these sampling devices from the effects of wind, for example by use of a mesh or membrane across the open end. The uptake rate of Ogawa[P] samplers was not associated with wind-speed resulting in a high correlation between estimated concentrations and observed analyser concentrations. The use of Palmes meshes in Ogawa[P] samplers reduced the cost of sampler preparation and removed uncertainty associated with the unknown manufacturing process for the commercially-prepared collection pads.
-
overestimation of urban nitrogen dioxide by Passive Diffusion tubes a comparative exposure and model study
Atmospheric Environment, 1999Co-Authors: Mathew R Heal, M A Odonoghue, J N CapeAbstract:Abstract A detailed comparative trial of Passive Diffusion tubes (PDT) for measurement of NO 2 in urban air has been undertaken in Edinburgh, UK. Acrylic, foil-wrapped and quartz tubes were exposed in parallel for 1-week and 4-week periods at three urban sites equipped with continuous analysers for NO, NO x and O 3 . Standard acrylic PDTs significantly overestimated NO 2 concentrations relative to chemiluminescence analysers, by an average of 27% over all sites for 1-week exposures. No significant difference was observed between standard and foil-wrapped acrylic tubes (both UV blocking). The mean ratio between quartz (UV transmitting) tubes and chemiluminescence analysers was 1.06. Quartz PDT data suggest a tendency for in situ photolysis to offset (but in a non-quantifiable way) the effect of chemical overestimation. The 4-week exposures yielded systematically lower NO 2 concentration than average NO 2 from four sequential 1-week exposures over the same period. The reduction in the apparent NO 2 sampling rate with time mostlikely arises from in situ photolysis of trapped NO 2 . Hourly NO 2 , NO and O 3 data for 20 1-week exposures were used as input to a numerical model of Diffusion tube operation incorporating chemical reaction between co-diffusing NO and O 3 within the tube. The mean calculated overestimation of 22% for NO 2 from the PDT model simulations is close to the average difference between acrylic PDT and analyser NO 2 concentrations (24% for the same exposure periods), showing that within-tube chemistry can account for observed discrepancies in NO 2 measurement between the two techniques. Overestimation by PDT generally increased as average NO 2 /NO x ratios decreased. Accurate quantitative correction of PDT measurements is not possible. Nevertheless, PDT NO 2 concentrations were correlated with both analyser NO 2 and NO x suggesting that acrylic PDTs retain a qualitative measure of NO 2 and NO x variation at a particular urban location.
-
a numerical evaluation of chemical interferences in the measurement of ambient nitrogen dioxide by Passive Diffusion samplers
Atmospheric Environment, 1997Co-Authors: Mathew R Heal, J N CapeAbstract:Abstract Passive Diffusion samplers containing tri-ethanolamine (TEA) as adsorbent are widely deployed for measuring NO2 concentrations in urban and rural air. In this study, a one-dimensional model of the sampler incorporating diffusive transport and chemical reaction has shown that NO2 concentrations are systematically overestimated as a result of chemical reactions in the tube, dominated by the reaction of NO with O3 to give NO2. The contribution of PAN and other potential interferents is shown to be small for British conditions. The extent of overestimation depends on the instantaneous [ NO ] [ NO 2 ] ratio and on the relative concentrations of NO and O3. In rural air, where [NO] The systematic error of within-tube chemistry is independent of, and acts in the same direction as, the possible overestimation caused by an effective shortening of Diffusion path length at high wind speeds and may be one explanation for Diffusion sampler overestimations previously attributed to wind effects. There appears to be no simple method for retrospectively correcting NO2 measurement data obtained using Diffusion tubes since the overestimate is not simply related to the average [ NO ] [ NO 2 ] nor [ NO ] [ O 3 ] ratios, but reflects the dynamical behaviour throughout the sampling period. Although Passive Diffusion samplers may give reliable concentration data for NOx in rural air, they cannot be used with confidence in polluted urban air to estimate NO2 concentrations.
Gian Camenisch - One of the best experts on this subject based on the ideXlab platform.
-
estimation of permeability by Passive Diffusion through caco 2 cell monolayers using the drugs lipophilicity and molecular weight
European Journal of Pharmaceutical Sciences, 1998Co-Authors: Han Van De Waterbeemd, Gian Camenisch, Jochem Alsenz, Gerd FolkersAbstract:Abstract A recently developed, new theoretical absorption model for Passive Diffusion through biological membranes describing the dependency of membrane permeability on lipophilicity and molecular size, predicts different sigmoid–hyperbolic permeability–lipophilicity relationships for different molecular weight ranges. This model has been tested with experimental in vitro cultured epithelial cell (Caco-2) permeability data for structurally diverse drugs differing in lipophilicity, ionization state and molecular size. These data were pooled with literature values. Using this simple physicochemical approach, the permeability of a compound through Caco-2 cells by Passive Diffusion can be predicted from the compounds' distribution coefficient in 1-octanol/water (log Doct) and its molecular weight (MW). Deviations from this expected behaviour may point to the involvement of biological components in the transport process, which may require further investigations.
