The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Per Artursson - One of the best experts on this subject based on the ideXlab platform.
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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, Brian J Houston, Edward H Kerns, 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.
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coexistence of passive and carrier mediated processes in Drug Transport
Nature Reviews Drug Discovery, 2010Co-Authors: Kiyohiko Sugano, Manfred Kansy, Gerhard F. Ecker, Stefanie Bendels, Per Artursson, Li Di, Bernard Faller, Holger Fischer, Alex Avdeef, Gregori GerebtzoffAbstract:The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a Drug. Although it is often accepted that many Drug substances are Transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane Drug Transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed Drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to Drug Transport activities across biological membranes.
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impact of extracellular protein binding on passive and active Drug Transport across caco 2 cells
Pharmaceutical Research, 2006Co-Authors: Per Artursson, Sibylle Neuhoff, Ismael Zamora, Annalena UngellAbstract:The objective of the study is to evaluate the mechanism behind alterations in passive and active Transport of Drugs in the presence of basolaterally applied extracellular protein using the Caco-2 cell model. The permeation across Caco-2 monolayers of two groups of compounds, Transported either solely by passive diffusion or partly also by active Transport in the secretory direction, was studied at two donor concentrations in the absence or presence of bovine serum albumin (BSA, 0–4%). Each group contained compounds with high or low protein binding (PB) capabilities and high or low absorption in humans (fraction absorbed, f a). The unbound fraction (f u) of each compound was determined by ultrafiltration. The Transport rate of the passively permeating compounds was the same in both apical-to-basolateral (absorptive) and basolateral-to-apical (secretory) directions in the absence of BSA. Basolaterally applied BSA increased the Transport rate in the absorptive direction and decreased it in the secretory direction for all compounds, in direct proportion to the extent of PB. The efflux ratios for the actively Transported compounds were reduced in the presence of BSA. Basolaterally applied BSA, which mimics in vivo PB, alters both passive and active Drug Transport in the Caco-2 cell model. Using C u in the calculations of Transport rate allowed elucidation of the different mechanisms behind these alterations. Our data also suggest that active secretory Transport for highly protein-bound compounds might have less effect in vivo than predicted from traditional Caco-2 cell models (without BSA).
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effect of molecular charge on intestinal epithelial Drug Transport ph dependent Transport of cationic Drugs
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Katrin Palm, Kristina Luthman, Jenny Ros, Johan Grasjo, Per ArturssonAbstract:The aim of this study was to investigate the effect of ionization on Drug Transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) Transported basic model Drug across Caco-2 cell monolayers was investigated. Both Drugs had p K a values in the physiological pH range. The permeability coefficients (P c ) of the model Drugs were obtained at varying apical buffer pHs, thus varying the degree of Drug ionization (from 5 to 95%). The relationship between P c and the fraction of the Drug in un-ionized form (f u ) was analyzed to delineate the permeability coefficients of the un-ionized (P c,u ) and ionized (P c,i ) forms of the Drugs. Theoretical estimates of the p K a values were also calculated from ionization energies for each model compound. For both Drugs, a linear increase in P c was observed with increasing f u . Transport of the un-ionized form was 150- and 30-fold more rapid than Transport of the ionized form for alfentanil and cimetidine, respectively. However, when f u u is
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effect of molecular charge on intestinal epithelial Drug Transport ph dependent Transport of cationic Drugs
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Katrin Palm, Kristina Luthman, Jenny Ros, Johan Grasjo, Per ArturssonAbstract:The aim of this study was to investigate the effect of ionization on Drug Transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) Transported basic model Drug across Caco-2 cell monolayers was investigated. Both Drugs had pK(a)values in the physiological pH range. The permeability coefficients (P(c)) of the model Drugs were obtained at varying apical buffer pHs, thus varying the degree of Drug ionization (from 5 to 95%). The relationship between P(c) and the fraction of the Drug in un-ionized form (f(u)) was analyzed to delineate the permeability coefficients of the un-ionized (P(c,u)) and ionized (P(c,i)) forms of the Drugs. Theoretical estimates of the pK(a) values were also calculated from ionization energies for each model compound. For both Drugs, a linear increase in P(c) was observed with increasing f(u). Transport of the un-ionized form was 150- and 30-fold more rapid than Transport of the ionized form for alfentanil and cimetidine, respectively. However, when f(u) <0.1, the contribution of the ionized form was significant. Because f(u) is <0.1 over the entire physiological pH range for a large number of Drugs, these results will have implications on predictions of in vivo intestinal Drug absorption both from in vitro studies in cell cultures and from computed structural properties of Drug molecules.
Kees Nooter - One of the best experts on this subject based on the ideXlab platform.
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chronic imatinib mesylate exposure leads to reduced intracellular Drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 Drug Transport pumps
Cancer Biology & Therapy, 2005Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees NooterAbstract:Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumours. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC Transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco-2 cells as an in vitro model for intestinal Drug Transport, we found that continuous exposure (up to 100 days) with imatinib (10 ?M) specifically upregulates the expression of ABCG2 (maximal ~17-fold) and ABCB1 (maximal ~5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco-2 cells resulted in a ~50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- an...
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chronic imatinib mesylate exposure leads to reduced intracellular Drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 Drug Transport pumps
Cancer Biology & Therapy, 2005Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees NooterAbstract:Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC Transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal Drug Transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these Drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that Drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic Drug resistance in cancer patients that are chronically treated with imatinib.
William N Charman - One of the best experts on this subject based on the ideXlab platform.
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intestinal lymph flow and lipid and Drug Transport scale allometrically from pre clinical species to humans
Frontiers in Physiology, 2020Co-Authors: Natalie L Trevaskis, William N Charman, Alistair B J Escott, Kian Liun Phang, Jiwon Hong, Kasiram Katneni, Susan A Charman, Anthony R J PhillipsAbstract:The intestinal lymphatic system Transports fluid, immune cells, dietary lipids, and highly lipophilic Drugs from the intestine to the systemic circulation. These Transport functions are important to health and when dysregulated contribute to pathology. This has generated significant interest in approaches to deliver Drugs to the lymphatics. Most of the current understanding of intestinal lymph flow, and lymphatic lipid and Drug Transport rates, comes from in vitro studies and in vivo animal studies. In contrast, intestinal lymphatic Transport studies in human subjects have been limited. Recently, three surgical patients had cannulation of the thoracic lymph duct for collection of lymph before and during a stepwise increase in enteral feed rate. We compared these data to studies where we previously enterally administered controlled quantities of lipid and the lipophilic Drug halofantrine to mice, rats and dogs and collected lymph and blood (plasma). The collected lymph was analyzed to compare lymph flow rate, triglyceride (TG) and Drug Transport rates, and plasma was analyzed for Drug concentrations, as a function of enteral lipid dose across species. Lymph flow rate, TG and Drug Transport increased with lipid administration in all species tested, and scaled allometrically according to the equation A = aM E where A is the lymph Transport parameter, M is animal body mass, a is constant and E is the allometric exponent. For lymph flow rate and TG Transport, the allometric exponents were 0.84-0.94 and 0.80-0.96, respectively. Accordingly, weight normalized lymph flow and TG mass Transport were generally lower in larger compared to smaller species. In comparison, mass Transport of Drug via lymph increased in a greater than proportional manner with species body mass with an exponent of ∼1.3. The supra-proportional increase in lymphatic Drug Transport with species body mass appeared to be due to increased partitioning of Drug into lymph rather than blood following absorption. Overall, this study proposes that intestinal lymphatic flow, and lymphatic lipid and Drug Transport in humans is most similar to species with higher body mass such as dogs and underestimated by studies in rodents. Notably, lymph flow and lipid Transport in humans can be predicted from animal data via allometric scaling suggesting the potential for similar relationships with Drug Transport.
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lipid based delivery systems and intestinal lymphatic Drug Transport a mechanistic update
Advanced Drug Delivery Reviews, 2008Co-Authors: Natalie L Trevaskis, William N Charman, Christopher J H PorterAbstract:Abstract After oral administration, the majority of Drug molecules are absorbed across the small intestine and enter the systemic circulation via the portal vein and the liver. For some highly lipophilic Drugs (typically log P > 5, lipid solubility > 50 mg/g), however, association with lymph lipoproteins in the enterocyte leads to Transport to the systemic circulation via the intestinal lymph. The attendant delivery benefits associated with lymphatic Drug Transport include a reduction in first-pass metabolism and lymphatic exposure to Drug concentrations orders of magnitude higher than that attained in systemic blood. In the current review we briefly describe the mechanisms by which Drug molecules access the lymph and the formulation strategies that may be utilised to enhance lymphatic Drug Transport. Specific focus is directed toward recent advances in understanding regarding the impact of lipid source (both endogenous and exogenous) and intracellular lipid trafficking pathways on lymphatic Drug Transport and enterocyte-based first-pass metabolism.
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lipids and lipid based formulations optimizing the oral delivery of lipophilic Drugs
Nature Reviews Drug Discovery, 2007Co-Authors: Christopher J H Porter, Natalie L Trevaskis, William N CharmanAbstract:Highly potent, but poorly water-soluble, Drug candidates are common outcomes of contemporary Drug discovery programmes and present a number of challenges to Drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic Drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic Drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance Drug solubilization in the intestinal milieu, recruit intestinal lymphatic Drug Transport (and thereby reduce first-pass Drug metabolism) and alter enterocyte-based Drug Transport and disposition.
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intestinal lymphatic Drug Transport an update
Advanced Drug Delivery Reviews, 2001Co-Authors: Christopher J H Porter, William N CharmanAbstract:The trend towards identification of poorly water-soluble and highly lipophilic candidate Drug molecules has led to an increase in interest in intestinal lymphatic Drug Transport. In this article we provide a brief background to the mechanism of access of Drugs to the intestinal lymph and the role of lipid digestion and absorption in the stimulation of lymphatic Transport. The ability of different lipid types to stimulate lymphatic Drug Transport, is addressed, concentrating specifically on the impact of the class, chain length and degree of unsaturation of co-administered lipids. Comment is also made as to the relevance of dosing different lipid volumes to the rat and the possible complications this may provide when trying to assess the likely extent of intestinal lymphatic Transport. Recent studies are described in which the extent of lymphatic Transport of a highly lipophilic antimalarial, halofantrine, was investigated after post-prandial administration to greyhound dogs. Finally the possible future directions for studies of intestinal lymphatic Transport are discussed, including the use of cell culture models and genetically modified animals.
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animal models for the study of intestinal lymphatic Drug Transport
Advanced Drug Delivery Reviews, 2001Co-Authors: Glenn A Edwards, Christopher J H Porter, Suzanne Mary Caliph, Shuimei Khoo, William N CharmanAbstract:Drug Transport via the intestinal lymphatic system has been shown to contribute to the absorption of a number of orally administered highly lipophilic Drugs. In order to investigate this phenomenon and assist in the development of improved oral formulations, the use of appropriate animal models is required. This paper reviews the use of various animal models for this purpose, and describes in detail the conscious rat and dog models used in our laboratory. The advantages and disadvantages of both small and large animal models are explored, as well as the factors which have been found to influence the outcome of intestinal lymphatic Drug Transport studies with these models.
Herman Burger - One of the best experts on this subject based on the ideXlab platform.
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chronic imatinib mesylate exposure leads to reduced intracellular Drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 Drug Transport pumps
Cancer Biology & Therapy, 2005Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees NooterAbstract:Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumours. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC Transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco-2 cells as an in vitro model for intestinal Drug Transport, we found that continuous exposure (up to 100 days) with imatinib (10 ?M) specifically upregulates the expression of ABCG2 (maximal ~17-fold) and ABCB1 (maximal ~5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco-2 cells resulted in a ~50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- an...
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chronic imatinib mesylate exposure leads to reduced intracellular Drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 Drug Transport pumps
Cancer Biology & Therapy, 2005Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees NooterAbstract:Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC Transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal Drug Transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these Drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that Drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic Drug resistance in cancer patients that are chronically treated with imatinib.
Katrin Palm - One of the best experts on this subject based on the ideXlab platform.
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effect of molecular charge on intestinal epithelial Drug Transport ph dependent Transport of cationic Drugs
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Katrin Palm, Kristina Luthman, Jenny Ros, Johan Grasjo, Per ArturssonAbstract:The aim of this study was to investigate the effect of ionization on Drug Transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) Transported basic model Drug across Caco-2 cell monolayers was investigated. Both Drugs had p K a values in the physiological pH range. The permeability coefficients (P c ) of the model Drugs were obtained at varying apical buffer pHs, thus varying the degree of Drug ionization (from 5 to 95%). The relationship between P c and the fraction of the Drug in un-ionized form (f u ) was analyzed to delineate the permeability coefficients of the un-ionized (P c,u ) and ionized (P c,i ) forms of the Drugs. Theoretical estimates of the p K a values were also calculated from ionization energies for each model compound. For both Drugs, a linear increase in P c was observed with increasing f u . Transport of the un-ionized form was 150- and 30-fold more rapid than Transport of the ionized form for alfentanil and cimetidine, respectively. However, when f u u is
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effect of molecular charge on intestinal epithelial Drug Transport ph dependent Transport of cationic Drugs
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Katrin Palm, Kristina Luthman, Jenny Ros, Johan Grasjo, Per ArturssonAbstract:The aim of this study was to investigate the effect of ionization on Drug Transport across the intestinal epithelium in order to include this effect in structure-absorption relationships. The pH-dependent permeation of one rapidly (alfentanil) and one slowly (cimetidine) Transported basic model Drug across Caco-2 cell monolayers was investigated. Both Drugs had pK(a)values in the physiological pH range. The permeability coefficients (P(c)) of the model Drugs were obtained at varying apical buffer pHs, thus varying the degree of Drug ionization (from 5 to 95%). The relationship between P(c) and the fraction of the Drug in un-ionized form (f(u)) was analyzed to delineate the permeability coefficients of the un-ionized (P(c,u)) and ionized (P(c,i)) forms of the Drugs. Theoretical estimates of the pK(a) values were also calculated from ionization energies for each model compound. For both Drugs, a linear increase in P(c) was observed with increasing f(u). Transport of the un-ionized form was 150- and 30-fold more rapid than Transport of the ionized form for alfentanil and cimetidine, respectively. However, when f(u) <0.1, the contribution of the ionized form was significant. Because f(u) is <0.1 over the entire physiological pH range for a large number of Drugs, these results will have implications on predictions of in vivo intestinal Drug absorption both from in vitro studies in cell cultures and from computed structural properties of Drug molecules.
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caco 2 monolayers in experimental and theoretical predictions of Drug Transport
Advanced Drug Delivery Reviews, 1996Co-Authors: Per Artursson, Katrin Palm, Kristina LuthmanAbstract:This review examines the use of Caco-2 monolayers in the prediction of intestinal Drug absorption. First, the different routes of Drug Transport in Caco-2 monolayers are compared with those seen in vivo. Second, the prediction of Drug absorption in vivo from Transport experiments in cell monolayers is discussed for different classes of Drugs. Finally, the use of Caco-2 monolayers as a reference model in physico-chemical and theoretical predictions of Drug absorption is discussed. We conclude that Caco-2 monolayers can be used to identify Drugs with potential absorption problems, and possibly also to select Drugs with optimal passive absorption characteristics from series of pharmacologically active molecules generated in Drug discovery programs.
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comparison between active and passive Drug Transport in human intestinal epithelial caco 2 cells in vitro and human jejunum in vivo
International Journal of Pharmaceutics, 1996Co-Authors: Hans Lennernas, Katrin Palm, U Fagerholm, Per ArturssonAbstract:Drug Transport rates in Caco-2 monolayers were compared with those obtained in the human jejunum in vivo. Permeability coefficients unbiased by the hydrodynamic conditions were calculated in order to allow direct comparison of the two models. The rapidly (passively) Transported Drugs naproxen, antipyrine and metoprolol had comparable permeability coefficients in Caco-2 cells and in human jejunum. The permeability coefficients of the slowly (passively) Transported, hydrophilic Drugs, terbutaline and atenolol, 79- and 27-fold lower, respectively, in Caco-2 cells than in jejunum. The carrier-mediated Transport rates of L-dopa, L-leucine and D-glucose were also much slower in Caco-2 cells than in human jejunum. The lower permeability of the actively Transported compounds and of atenolol and terbutaline is consistent with the colonic origin of the Caco-2 cells. The results indicate that Caco-2 monolayers can be used to predict passive Drug Transport in humans, while prediction of Transport by carrier-mediated systems may require a scaling factor, due to a low expression of carriers in this cell line.
