Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network

Vinarov, Zahari; Abrahamsson, Bertil; Artursson, Per; Batchelor, Hannah; Berben, Philippe; Bernkop‐Schnürch, Andreas; Butler, James; Ceulemans, Jens; Davies, Nigel; Dupont, Didier; Flaten, Gøril Eide; Fotaki, Nikoletta; Griffin, Brendan T.; Jannin, Vincent; Keemink, Janneke; Kesisoglou, Filippos; Koziolek, Mirko; Kuentz, Martin; Mackie, Alan; Meléndez-Martínez, Antonio J.; McAllister, Mark; Müllertz, Anette; O’Driscoll, Caitriona M.; Parrott, Neil; Paszkowska, Jadwiga; Pávek, Petr; Porter, Christopher John; Reppas, Christos; Stillhart, Cordula; Sugano, Kiyohiko; Toader, Elena; Valentová, Kateřina; Wildt, Saskia N. de; Wilson, Clive G.; Augustijns, Patrick

doi:10.1016/j.addr.2021.02.001

Cited by 97 publications

(76 citation statements)

References 459 publications

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“… 4 , 5 Consequently, the extent of intestinal drug absorption may be influenced by the site of drug release. 6 , 7 The quantification of P-gp along the intestinal tract can, therefore, aid in predicting the intestinal drug absorption for drugs that are P-gp substrates.…”

Section: Introductionmentioning

confidence: 99%

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

et al. 2021

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Intestinal efflux transporters affect the gastrointestinal processing of many drugs but further data on their intestinal expression levels are required. Relative mRNA expression and relative and absolute protein expression data of transporters are commonly measured by real-time polymerase chain reaction (RT-PCR), Western blot and mass spectrometry-based targeted proteomics techniques. All of these methods, however, have their own strengths and limitations, and therefore, validation for optimized quantification methods is needed. As such, the identification of the most appropriate technique is necessary to effectively translate preclinical findings to first-in-human trials. In this study, the mRNA expression and protein levels of the efflux transporter P-glycoprotein (P-gp) in jejunal and ileal epithelia of 30 male and female human subjects, and the duodenal, jejunal, ileal and colonic tissues in 48 Wistar rats were quantified using RT-PCR, Western blot and liquid chromatography-tandem mass spectrometry (LC-MS/MS). A similar sex difference was observed in the expression of small intestinal P-gp in humans and Wistar rats where P-gp was higher in males than females with an increasing trend from the proximal to the distal parts in both species. A strong positive linear correlation was determined between the Western blot data and LC-MS/MS data in the small intestine of humans ( R 2 = 0.85). Conflicting results, however, were shown in rat small intestinal and colonic P-gp expression between the techniques ( R 2 = 0.29 and 0.05, respectively). In RT-PCR and Western blot, an internal reference protein is experimentally required; here, beta-actin was used which is innately variable along the intestinal tract. Quantification via LC-MS/MS can provide data on P-gp expression without the need for an internal reference protein and consequently, can give higher confidence on the expression levels of P-gp along the intestinal tract. Overall, these findings highlight similar trends between the species and suggest that the Wistar rat is an appropriate preclinical animal model to predict the oral drug absorption of P-gp substrates in the human small intestine.

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Section: Introductionmentioning

confidence: 99%

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

et al. 2021

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“…There is a recognised knowledge gap about the amount and distribution of free fluid in the GIT of the paediatric population [ 36 , 37 , 38 ], resulting in a need to generate physiological data to underpin the development of age appropriate physiologically based pharmacokinetic (PBPK) models. This would improve prediction of drug performance in children, as paediatric clinical trials often face ethical constraints [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

et al. 2021

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Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in the paediatric colon. MRI datasets from 28 fasted (aged 0–15 years) and 18 fluid-fed (aged 10–16 years) paediatric participants were acquired during routine clinical care. A series of 2D- and 3D-based software protocols were used to measure colonic fluid volume and localisation. The paediatric colon contained a mean volume of 22.5 mL ± 41.3 mL fluid, (range 0–167.5 mL, median volume 0.80 mL) in 15.5 ± 17.5 discreet fluid pockets (median 12). The proportion of the fluid pockets larger than 1 mL was 9.6%, which contributed to 94.5% of the total fluid volume observed. No correlation was detected between all-ages and colonic fluid volume, nor was a difference in colonic fluid volumes observed based on sex, fed state or age group based on ICH-classifications. This study quantified fluid volumes within the paediatric colon, and these data will aid and accelerate the development of biorelevant tools to progress paediatric drug development for colon-targeting formulations.

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“…Thus, specialists in the field must rely on their knowledge to adapt formulations to suit the pharmaceutical needs of the individual [50]. There are many factors to consider during personalised formulation design, some include: patient's swallowing capacity, flavour preferences, required drug dose, required drug release kinetics, presence of disease, sex, age, motor skills, and coadministered medications [184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199]. ML has the capacity to consider all these factors and predict optimal formulation design features based on an individual's requirements [154,[200][201][202].…”

Section: Machine Learning In the Pre-printing Stagementioning

confidence: 99%

Harnessing artificial intelligence for the next generation of 3D printed medicines

Elbadawi

McCoubrey

Gavins

et al. 2021

Advanced Drug Delivery Reviews

102

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Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network

Cited by 97 publications

References 459 publications

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

Harnessing artificial intelligence for the next generation of 3D printed medicines

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