Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications

Abstract

A thorough knowledge of the newborn (age, birth to 1 month postpartum) infant's gastrointestinal tract (GIT) is critical to the evaluation of the absorption, distribution, metabolism, and excretion (ADME) of orally administered drugs in this population. Developmental changes in the GIT during the newborn period are important for nutrient uptake as well as the disposition of orally administered medications. Some aspects of gastrointestinal function do not mature until driven by increased dietary complexity and nutritional demands later in the postnatal period. The functionalities present at birth, and subsequent maturation, can also impact the ADME parameters of orally administered compounds. This review will examine some specific contributors to the ADME processes in human neonates, as well as what is currently understood about the drivers for their maturation. Key species differences will be highlighted, with a focus on laboratory animals used in juvenile toxicity studies. Because of the gaps and inconsistencies in our knowledge, we will also highlight areas where additional study is warranted to better inform the appropriate use of medicines specifically intended for neonates.

Modeling age‐dependent developmental changes in the expression of genes involved in citrulline synthesis using pig enteroids

“…Due to its intestinal development and physiology, the pig is considered a more appropriate species to model human infant (patho)physiological processes than rodents. Not only do pigs and humans have more mature digestive functions shortly after birth than rodents (Downes, 2018; Neal‐Kluever, Fisher, Grylack, Kakiuchi‐Kiyota, & Halpern, 2019), but in mice the elongation of villi and crypts, and the establishment of a generative zone are not fully completed until after weaning (Hirano, 1986) whereas in pigs villi are fully formed 10 days before term (~90% gestation)(Robinson et al., 2018). Whereas premature pigs are susceptible to dietary induction of NEC (Sangild et al., 2006), recapitulating many of the key elements observed in humans, the rodent NEC models require additional conditions (including hypothermia, hypoxia, and endotoxemia) to simulate this disease (Premkumar et al., 2014).…”

“…Due to its intestinal development and physiology, the pig is considered a more appropriate species to model human infant (patho)physiological processes than rodents. Not only do pigs and humans have more mature digestive functions shortly after birth than rodents (Downes, 2018;Neal-Kluever, Fisher, Grylack, Kakiuchi-Kiyota, & Halpern, 2019), but in mice the elongation of villi and crypts, and the establishment of a generative zone are not fully completed until after weaning (Hirano, 1986) whereas in pigs villi are fully formed 10 days before term F I G U R E 1 Pathway for the endogenous synthesis of arginine. Metabolites (circles) and enzymes (hexagons) are depicted.…”

Lipid Composition, Digestion, and Absorption Differences among Neonatal Feeding Strategies: Potential Implications for Intestinal Inflammation in Preterm Infants

“…The chief neonatal primary bile acids, cholic acid and chenodeoxycholic acid [88], are predominantly conjugated to taurine, as the glycine conjugation process in the liver is not yet developmentally mature [91]. While there is passive uptake of BAs in the neonate, luminal bile salt concentration does not increase significantly until later in infancy, as active transport and enterohepatic circulation of these BAs is hampered during the neonatal period [92]. Interestingly, despite both groups harboring low levels of bile salts, preterm infants fed HM absorb lipids at a higher rate than those fed formula [93].…”

Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

“…The aim of the current review is to provide an overview of the ontogeny and cross-species differences of pathways involved in ADME in the developing kidney in preterm and term neonatal animals and children. This review is part of a multisector collaborative research effort coordinated by the Health and Environmental Sciences Institute to increase the knowledge base in the nonclinical space to better inform clinical treatment decisions made for the pediatric population (De Schaepdrijver et al, 2019;Hausner et al, 2019;Neal-Kluever et al, 2019). The ontogeny and cross-species differences of ADME-related processes in the liver and other organs will be covered by other reviews.…”