Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

Abstract

Drug-drug interactions (DDIs) occur when the action of one drug interferes with or alters the activity of another drug taken concomitantly. This can lead to decreased drug efficacy or increased toxicity. Because of DDIs, physicians in the clinical practice attempt to avoid potential interactions when multiple drugs are coadministrated; however, there is still a large knowledge gap in understanding how drugs taken in the past can contribute to DDIs in the future. The goal of this study was to investigate the consequence of neonatal drug exposure on efficacy of other drugs administered up through adult life. We selected a mouse model to test phenobarbital exposure at a neonatal age and its impact on efficacy of omeprazole in adult life. The results of our experiment show an observed decrease in omeprazole's ability to raise gastric pH in adult mice that received single or multiple doses of phenobarbital at a neonatal age. This effect may be associated with the permanent induction of cytochrome P450 enzymes in adult liver after neonatal phenobarbital treatment. Our data indicates that DDIs may result from drugs administered in the past in an animal model and should prompt re-evaluation of how DDIs are viewed and how to avoid long-term DDIs in clinical practice.

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

“…A similar phenomenon on long-term impact of CYP expression by neonatal exposure to drugs has also been observed in mice in later studies (Tien et al, 2015(Tien et al, , 2017Piekos et al, 2018).…”

“…When mice were older than the age window, no matter how high doses were used, exposure to phenobarbital couldn't cause long-term induction of CYP expression. Phenobarbital treatment at a neonatal age can also result in decreased efficacy in acid suppression in adult mouse stomach by omeprazole, a proton pump inhibitor drug, due to increased metabolism of omeprazole by induced CYP enzymes (Tien et al, 2017). Omeprazole is known to be metabolized by CYP enzymes, mainly by CYP2C19 and 3A4 in human liver (Ishizaki et al, 1999).…”

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

“…Previous work has shown that direct activation using 1,4-bis[2-(3,5-dichloropyridoyloxy)] benzene, a murine-specific CAR ligand, at the neonatal age also produces permanent alterations to P450 expression (Li et al, 2016a) and function in adulthood, which alters the efficacy of zoxazolamine administered later in life (Chen et al, 2012). Phenobarbital exposure at the neonatal age also caused a decrease in efficacy of omeprazole administered to adult mice, suggesting its role in a possible nonconventional DDI (Tien et al, 2017). Due to phenytoin's ability to cause CAR activation, we presumed that neonatal exposure would also cause a similar permanent alteration to represents GAPDH expression set to 1 (n = 4-6).…”

“…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.…”