Date of Completion

5-4-2018

Embargo Period

5-4-2019

Keywords

Pharmacology

Major Advisor

Xiao-bo Zhong

Associate Advisor

Charles Giardina

Associate Advisor

Warren Ku

Associate Advisor

Jose Manautou

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Adverse reactions or lack of therapeutic efficacy are commonly encountered challenges when prescribing pharmaceutical drugs to patients. These undesirable outcomes highlight the large amount of interindividual variability in drug responses, and can often be attributed to differences in drug metabolism and clearance rates among patients. Patient age and current medication usage are two variables that can increase or decrease the expression and activity of drug metabolism by cytochrome P450 enzymes (CYPs), thus impacting responses to other drugs. Neonates, infants, and children, express CYP enzymes at different levels than adults due to immature liver functions, and this causes drug responses to differ in pediatric populations. Because infants and children are not typically included in clinical drug trials, there is a significant knowledge gap in understanding how CYP expression and liver function may be impacted by drug treatment in early postnatal life. Antiepileptic drugs (AEDs) are commonly administered to newborns, infants, and children suffering from acute seizures or chronic epilepsy, however these medications are known to induce the expression of drug-metabolizing CYPs. This work has explored the consequences of exposure to two AEDs, phenobarbital and phenytoin, on the expression and activity of drug-metabolizing CYPs in the liver during postnatal development in mice. Short-term, as well as long-term, effects on gene and protein expression profiles and enzymatic activities were evaluated. Our results demonstrate that responses to AED treatment differ significantly in neonatal mice compared to adults in terms of CYP inducibility and liver functions that were altered. Additionally, exposure to AEDs at neonatal ages may cause permanent effects on gene and protein expression in the liver in adulthood, which could impact drug efficacy and susceptibility to liver diseases later in life. These differential effects may be due to epigenetic modifications that are susceptible to alteration by drug treatment in the maturing liver that does not occur in the fully differentiated adult liver. Overall, these studies highlight a critical need for a better understanding of pharmacokinetic regulation in pediatric populations, as drug responses in adults cannot be used for accurate prediction or extrapolation of drug responses in infants and children.

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