Evidence-based approach to assess passive diffusion and carrier-mediated drug transport

Di, Li; Artursson, Per; Avdeef, Alex; Ecker, Gerhard F.; Faller, Bernard; Fischer, Holger; Houston, J. Brian; Kansy, Manfred; Kerns, Edward H.; Krämer, Stefanie-Dorothea; Lennernäs, Hans; Sugano, Kiyohiko

doi:10.1016/j.drudis.2012.03.015

Cited by 138 publications

(99 citation statements)

References 53 publications

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“…Physiological differences between the GI tract and the BBB, however, make this concept less translatable. Many articles have compared permeability values from in silico predictions, in vitro cell models, in situ methods, and in vivo methods (Levin 1980;Abbott 2004b;Liu et al 2004;Bickel 2005;Garberg et al 2005;Summerfield et al 2007;Abbott et al 2008;Di et al 2009;Friden et al 2009b;Hammarlund-Udenaes et al 2009;Fan et al 2010;Mensch et al 2010a;Mensch et al 2010b;Avdeef 2011;Avdeef and Sun 2011;Chen et al 2011;Broccatelli et al 2012;Di et al 2012;Lanevskij et al 2013). Quite commonly, methods measuring the rate of permeation are compared with those measuring the extent of permeation (Pardridge 2004;Hakkarainen et al 2010).…”

Section: What and Whymentioning

confidence: 98%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain . This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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Section: What and Whymentioning

confidence: 98%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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“…However, this is controversial and is argued against persuasively by a variety of authors who have refuted Kell's contentions and support the broader view that, while carriers play a role, many drugs enter via passive diffusion [50][51][52][53] . Many of the concepts of diffusion through a lipid bilayer as described by Kramer and by Balaz 50,51,54 most likely apply to bacterial CM as well.…”

Section: Do Cytoplasmic Membrane Transporters Play a Role In Antibiotmentioning

confidence: 99%

A Gestalt approach to Gram-negative entry

Silver¹

2016

Bioorganic & Medicinal Chemistry

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“…Although active transport is important, passive diffusion is the major route for drugs to access the brain from the bloodstream 17. Substantial curation of a recent dataset18 supported by specialized databases was required to build our passive BBB‐permeation model (refer to Methods S2 in the Supporting Information).…”

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A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

2016

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Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED‐Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED‐Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

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Evidence-based approach to assess passive diffusion and carrier-mediated drug transport

Cited by 138 publications

References 53 publications

Pharmacokinetic Concepts in Brain Drug Delivery

Pharmacokinetic Concepts in Brain Drug Delivery

A Gestalt approach to Gram-negative entry

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

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