Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only

Kell, Douglas B.; Dobson, Paul D.; Oliver, Stephen G.

doi:10.1016/j.drudis.2011.05.010

Cited by 173 publications

(153 citation statements)

References 153 publications

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“…For both compounds, predictions employing the permeabilities derived from the HEK-293 cell data are in agreement with that observed in the MDCK-LE Transwell system across three different pHs. The translatability in passive permeability parameters between HEK-293 cells and MDCK-LE cells is at odds with recent speculation that passive permeation is a transporter-mediated phenomenon (Dobson and Kell, 2008;Kell et al, 2011). With regard to the mathematical model, we note that, although observed permeability (P obs ) collapses into its more phenomenological form ðJ % P obs ðC o 2 C i ÞÞ, the term P obs is itself a complex formula of physiochemical parameters: neutral passive permeability P n , ionized passive permeability P, the pK a of the compound, and physiologic parameters: the underlying membrane potential of the cell f and local pH.…”

Section: Resultsmentioning

confidence: 95%

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

et al. 2014

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In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the NernstPlanck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties.

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Section: Resultsmentioning

confidence: 95%

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

et al. 2014

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“…While permeability of drug compounds through the intestinal membrane is a complex process 29 . The mechanism of drug transport in cell cultures is by passive transcellular and paracellular transport and active-carrier mediate transport 31 . The intestinal permeability of a drug can be evaluated by many techniques 29 .…”

Section: Intestinal Permeability By Cell Culturementioning

confidence: 99%

Applications of cell culture studies in pharmaceutical technology

Şahin¹,

Mesut²,

Özsoy³

2017

actapharm

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“…While it was traditionally thought that drugs enter cells by passive diffusion it is now widely acknowledged that transporters (proteins integral to the plasma membrane facilitating the movement of compounds in and out of cells) are major determinants of drug absorption and elimination, as well as entry into the target organ (Fig. 2) [57][58][59][60]. The potential role of drug transporters in resistance to antiepileptic drug therapy is currently being intensely discussed [61].…”

Section: Role Of Variation In Adme Genes For Pharmacoresponsementioning

confidence: 99%

Genetic Biomarkers in Epilepsy

et al. 2014

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The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.

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Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only

Cited by 173 publications

References 153 publications

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

Applications of cell culture studies in pharmaceutical technology

Genetic Biomarkers in Epilepsy

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