The NIH Funding Opportunity PAR-13-306: Developmental Pharmacology and Toxicology: Role of Ontogeny emphasizes the urgency of addressing the issue of short- or long-term alterations of genes involved in pharmacokinetics in response to drug exposure in early development. Physicians use drugs to treat various diseases in neonates and infants. However, the current clinical practices have not considered the potential short- or long-term consequences on the patient's ability to metabolize drugs during adulthood who have received drug treatment early in life. A major reason is the lack of basic research to understand the consequences (short- or long-term) that drug exposure in early life has on drug metabolism, therapeutic efficacy, and potential for drug-induced toxicity. The goal in this study is to understand the short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity. Based on the previous publications and our preliminary data, we have formed a central hypothesis that early life exposure to drugs that have the ability to activate nuclear receptors can result in either immediate (short-term) or persistent (long-term) alterations of expression and functions of certain drug metabolizing enzymes, further leading to alterations in therapeutic efficacy and sensitivity to toxicity of other drugs. This effect is dependent on the ability of the drug exposur with a certain dose at a specific age to alter epigenetic memory in liver. We have formed an investigator team with experts necessary to accomplish the proposed works. We will use phenobarbital for drug exposure at early life, omeprazole and midazolam for therapeutic efficacy, and acetaminophen for hepatotoxicity. We will focus on P450s (such as Cyp2b, Cyp2c, and Cyp3a) as our target drug metabolizing enzymes and the mouse as our animal model to examine the central hypothesis in the following specific aims.
Aim 1 will determine the short- or long-term impacts of drug exposure at early life on drug metabolism.
Aim 2 will determine the short- or long-term impacts of drug exposure at early life on therapeutic efficacy.
Aim 3 will determine the short- or long-term impacts of drug exposure at early life on drug-induced hepatotoxicity. After completion of the specific aims, we will fill the knowledge gaps on the short or long-term impacts of drug exposure at early life on drug metabolism. Such knowledge is critical for developmental pharmacology and toxicology to better predict outcomes of drug exposure at early ages on drug responses and sensitivity to drug-induced toxicity throughout the lifetime.
The current application serves as a proof-of-concept study to determine the short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity in animal models. Once the basic knowledge is established in animal models, the information can be used as a guide for clinical studies in humans to select the right drugs and appropriate ages of patients to evaluate the short- or long-term impacts of drug exposure at early life on drug therapy.
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