Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

Abstract

Purpose of review As the number of patients taking more than one medication concurrently continues to increase, predicting and preventing drug-drug interactions (DDIs) is now more important than ever. Administration of one drug can cause changes in the expression and activity of drug metabolizing enzymes (DMEs) and alter the efficacy or toxicity of other medications that are substrates for these enzymes, resulting in a DDI. In today’s medical practice, potential DDIs are evaluated based on the current medications a patient is taking with little regard to drugs the patient has been exposed to in the past. The purpose of this review is to discuss potential impacts of drug treatment at neonatal ages on the variability of drug metabolism and DDIs in adult life. Recent findings Existing evidence from the last thirty years has shown that exposure to certain xenobiotics during neonatal life has the potential to persistently alter DME expression through adult life. With recent advancements in the understanding of epigenetic regulation on gene expression, this phenomenon is resurfacing in the scientific community in hopes of defining possible mechanisms. Exposure to compounds that have the ability to bind nuclear receptors and trigger epigenetic modifications at neonatal and pediatric ages may have long-term, if not permanent, consequences on gene expression and DME activity. Summary The information summarized in this review should challenge the way current healthcare providers assess DDI potential and may offer an explanation to the significant interindividual variability in drug metabolism that is observed among patients.

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

“…Whether the capacity for enzymatic induction varies at different ages during postnatal liver maturation is also not understood. Several studies have additionally suggested neonatal exposures to inducer drugs, particularly the antiepileptic drug (AED) phenobarbital, can cause permanent alterations to expression and activities of P450s in adult rodents Shapiro, 1996, 2005;Tien et al, 2015Tien et al, , 2017Piekos et al, 2017). There also appears to be a window of sensitivity during neonatal life that allows the imprinting of lasting changes to P450 expression following treatment (Tien et al, 2015).…”

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy

“…Mechanism. The latest literature suggests that persistent epigenetic changes in the promoters of CAR target genes, including Cyp2b10, are responsible for prolonged induction within the F0 generation in the liver (Chen et al, 2012;Peng and Zhong, 2015;Tien et al, 2015Tien et al, , 2017Li et al, 2016;Piekos et al, 2017;Lodato et al, 2018). Our work indicates that at least some of these effects may have been driven by activator accumulation rather than by stable DNA modifications.…”

Neonatal pharmacology and clinical implications

“…Mechanisms regulating paediatric gene expression and induction may also differ from those of adults. Drug metabolism occurs through phase I and phase II reactions, which, in newborns and children, are not entirely developed processes 35…”