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Garberg, Per; Eriksson, Peder; Schipper, Nicolaas; Sjöström, Brita

doi:10.1023/a:1018838121975

Cited by 23 publications

(4 citation statements)

References 3 publications

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“…Caco-2 assay has provided higher speed screening, but unfortunately the speed is still not sufficient for ultra-HTS due to its slow growth 22) and the requirement for manual assay procedures. 23) Based on the growing recognition that assays based on Caco-2 cells remain relatively low throughput methods, 4,[22][23][24][25] the parallel artificial membrane permeation assay 24) and the immobilized-artificial-membrane chromatography system 25) have also been developed to assess the affinity to the biological membrane. These systems might provide higher speed, but the data they produce are essentially similar to the partition coefficient between lipid and water.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Sakaeda

Okamura

Nagata

et al. 2001

Biological & Pharmaceutical Bulletin

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This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDR1 (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.

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Section: Discussionmentioning

confidence: 99%

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Sakaeda

Okamura

Nagata

et al. 2001

Biological & Pharmaceutical Bulletin

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“…Fortunately, there are many screening techniques based on these properties which can be used to improve the ability to recognize which compounds may be bioavailable. For example, to identify absorption issues, there are three approaches: (1) computational models, (2) direct modelssuch as screens for poor solubility with high throughput turbidimetric solubility, and (3) in vitro evaluations of permeability that use Caco-2 cells or in situ gut loop. , To characterize metabolism parameters such as metabolic clearance and first-pass metabolism, scientists use metabolic screens based on liver enzyme preparations (S9 and microsomes) or hepatocytes. , In vitro absorption and metabolism studies can be automated and thus have sufficient throughput capacity to screen a much larger number of compounds than by in vivo studies. − In vitro screens provide specific information, i.e., rates of permeability and metabolism, in a very timely manner, although there are limitations in the depth of this information and more extensive studies are generally warranted once compounds have been identified for further development.…”

Section: Introductionmentioning

confidence: 99%

Graphical Model for Estimating Oral Bioavailability of Drugs in Humans and Other Species from Their Caco-2 Permeability and in Vitro Liver Enzyme Metabolic Stability Rates

2001

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This paper describes a graphical model for simplifying in vitro absorption, metabolism, distribution, and elimination (ADME) data analysis through the estimation of oral bioavailability (%F) of drugs in humans and other species. This model integrates existing in vitro ADME data, such as Caco-2 permeability (P(app)) and metabolic stability (percent remaining - %R) in liver S9 or microsomes, to estimate %F into groups of low, medium, or high regions. To test the predictive accuracy of our model, we examined 21 drugs and drug candidates with a wide range of oral bioavailability values, which represent approximately 10 different therapeutic areas in humans, rats, dogs, and guinea pigs. In vitro data from model compounds were used to define the boundaries of the low, medium, and high regions of the %F estimation plot. On the basis of the in vitro data, warfarin (93%), indomethacin (98%), timolol (50%), and carbamazepine (70%) were assigned to the high %F region; propranolol (26%) and metoprolol (38%) to medium %F region; and verapamil (22%) and mannitol (18%) to the low %F region. Similarly, the %F of 11 drug candidates from Elastase Inhibitor, NK1/NK2 antagonist, and anti-viral projects in rats, guinea pigs, and dogs were correctly estimated. This model estimates the oral bioavailability ranges of neutral, polar, esters, acidic, and basic drugs in all species. For a large number of drug candidates, this graphical model provides a tool to estimate human oral bioavailability from in vitro ADME data. When combined with the high throughput in vitro ADME screening process, it has the potential to significantly accelerate the processes of lead identification and optimization.

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“…Most of these tools can be automated for high throughput applications (Garberg et al 1999 ). Because it is very difficult to develop a single in vitro system that can simulate the human in vivo setting, various in vitro assays are usually performed to investigate specific mechanisms (Abbott et al 2008 ).…”

Section: Reviewmentioning

confidence: 99%

Modeling bioavailability to organs protected by biological barriers

Quignot

2013

In Silico Pharmacol.

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Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human.Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters).On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction.In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models.We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.

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Cited by 23 publications

References 3 publications

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Graphical Model for Estimating Oral Bioavailability of Drugs in Humans and Other Species from Their Caco-2 Permeability and in Vitro Liver Enzyme Metabolic Stability Rates

Modeling bioavailability to organs protected by biological barriers

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