Variable drug disposition is a well recognized cause of altered drug efficacy and impaired safety. While some of the causes of this variability are known, much of it is still unexplained;consequently, many of the adverse drug reactions and drug efficacy determinants are still unpredictable. Since drug metabolism is a primary determinant of pharmacokinetics and most clinically serious drug-interactions are the result of alterations in drug metabolism, we wish to evaluate additional mechanisms that regulate the expression of the drug metabolizing enzymes. One important factor that contributes to variable drug metabolism is developmental change in the expression of the cytochrome P450 (CYP450) enzymes;this is a particularly important factor to consider in infants and young children. The central hypothesis of this proposal is that endogenous microRNAs (miRNAs) regulate developmental changes in the expression of key drug metabolizing enzymes, and thereby, altering drug exposure. Endogenous miRNAs are small non-coding RNAs that regulate gene and protein expression;this includes the important role of developmental regulation of tissue-specific gene expression. Our hypothesis is based on our preliminary data that suggest that miRNAs also regulate key CYP drug metabolizing enzymes. Our long-range goal is to improve the efficacy and safety of therapeutic drugs by better understanding and then reducing interindividual pharmacokinetic variability. We will test our hypotheses through the following specific aims: 1) To identify miRNAs that are predicted to control hepatic drug metabolism. The results of this bioinformatic effort will have broad biological relevance to the understanding of this important class of enzymes. 2) To determine the changes in global miRNA expression patterns that occur during the development of hepatic CYP450 activity. These studies will focus on the human fetal, neonatal/pediatric, and adult periods. 3) To identify miRNA expression patterns that are associated with the documented developmental changes in a single, but critical drug-metabolizing enzyme: CYP2D6. 4) To use in vitro miRNA bioassays to functionally test the predicted miRNA regulation of CYP2D6 expression. This project is highly innovative because it addresses the developmental variation seen in drug metabolism using new molecular mechanisms inherent in control by miRNA. These efforts may also have important implications for interindividual transporter, receptor, and signaling variability in children and adults. We have assembled a team of investigators that have well-recognized expertise in clinical pharmacology, molecular biology and bioinformatics. As part of this team, we have access to a wealth of appropriately consented clinical samples that will enable us to translate our findings directly into human studies. A better understanding of the developmental control mechanisms of the human hepatic CYP450 enzymes will likely improve our understanding of the developmental changes that occur in human drug metabolism. Ultimately, this should lead to improved therapeutic drug dosing strategies, particularly during critical times of developmental change.
We will be studying the underlying mechanisms that contribute to adverse drug reactions and poor drug efficacy. We will determine the role of small endogenous microRNAs in the regulation of liver drug metabolizing enzymes. These studies should help us better understand the interindividual variability in drug responses, and consequently improve drug therapies.
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