A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age‐dependent differences in absorption

Abstract

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption. Furthermore, differences between intestinal drug transport processes of children and adults were explored as well as the possible impact of age. Fresh terminal ileal leftover tissues from both children and adults were collected during surgery and prepared for Ussing chamber experiments. Paracellular (enalaprilat), transcellular (propranolol), and carrier‐mediated drug transport by MDR1 (talinolol) and BCRP (rosuvastatin) were determined with the Ussing chamber methodology. We calculated apparent permeability coefficients and efflux ratios and explored their relationship with postnatal age. The success rate for the Ussing chamber experiments, as determined by electrophysiological measurements, was similar between children (58%, N = 15, median age: 44 weeks; range 8 weeks to 17 years) and adults (67%, N = 13). Mean serosal to mucosal transport of talinolol by MDR1 and rosuvastatin by BCRP was higher in adult than in pediatric tissues (p = 0.0005 and p = 0.0091). In contrast, within our pediatric cohort, there was no clear correlation for efflux transport across different ages. In conclusion, the Ussing chamber is a suitable model to explore pediatric intestinal drug absorption and can be used to further elucidate ontogeny of individual intestinal pharmacokinetic processes like drug metabolism and transport.

Gut-on-a-Chip Research for Drug Development: Implications of Chip Design on Preclinical Oral Bioavailability or Intestinal Disease Studies

“…These organoid-derived monolayers show higher expression and functionality of major pharmacokinetic enzymes and transporters compared to Caco-2 monolayers, at levels close to the in vivo human intestine [ 12 ]. Alternative to these cell-based in vitro research models, ex vivo tissue-based models such as the Ussing chamber [ 13 , 14 , 15 ], the everted sac model [ 16 ] and the InTESTine™ system [ 17 , 18 ] or animal models are also used to study drug-related processes in the gut. Although these models reflect the true intestinal physiology, they are limited in throughput and lifespan (ex vivo) or ethics and translatability to humans (animal models).…”

Characterization of neonatal and infant enterostomy fluids - part II: Drug solubility

“…Despite significant progress in the predictive in vitro and in silico simulation of drug absorption in preclinical drug development, physiological changes related to disease, medication or age are currently poorly implemented due to the lack of reference data 13 . To advance the development of oral drugs tailored to the paediatric population 14,15 , for instance, recent studies have explored different absorption-related aspects of the gastrointestinal physiology in children, including fluid volume 16,17 , fluid composition 18,19 , and drug transporter and metabolic enzyme ontogeny 20,21 . In addition, Maharaj Pagina 3 van 28 et al 22 designed neonatal and pediatric SIF to explore drug solubility in children.…”

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

“…The numerous complexities in intestinal drug absorption, including known and as yet poorly understood physiological processes and physicochemical properties of the drug, are well-recognized, and research is needed to fill gaps in in vitro as well as in silico methods to predict oral drug absorption . Changes in gut physiology (e.g., due to disease, , sex differences, , age, , and food effects) and new knowledge in gut physiology (e.g., regional expression and activity of intestinal drug metabolizing enzymes and transporters) are important considerations to improve predictions of oral absorption in health and disease. Additionally, the active pharmaceutical ingredient (API) itself along with its oral formulation design greatly impacts oral absorption.…”