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Impact on Drug Responses in Adult Life by Drug Treatment at the Neonatal Age

The cytochrome P450 enzymes (P450s) are responsible for the metabolism of 75% of drugs currently on the market. However, significant interindividual variations in the enzyme activities of several P450s, including CYP3A4, CYP2B6, CYP2C9, and CYP2C19 exist in the general population. The differences in drug metabolism rates between people alter plasma drug exposure, and may account for the high incidences of adverse drug reactions or low therapeutic efficacy, which are difficult to predict. Identification of factors contributing to these variations is critical to develop strategies to better predict drug response. Several studies in animal models over the past 30 years have proven that adult basal P450 expression is permanently induced following neonatal exposure to the antiepileptic drug phenobarbital. Recently, our own study demonstrated that neonatal treatment with phenobarbital resulted in decreased therapeutic efficacy of omeprazole in proton‐pump inhibition to raise gastric pH in stomachs of adult mice. This decreased efficacy of omeprazole correlated with an upregulation of the P450s that mediate omeprazole metabolism, CYP3A11 and CYP2C29, in the liver of adult mice that received treatment with phenobarbital at the neonatal age. There is now a critical need to investigate whether neonatal treatment with different drugs produces the same permanent variations in P450 expression and metabolism of other drugs administered later in life. We hypothesize that phenytoin, another antiepileptic drug that induces P450s in mice and humans, will also cause permanent overexpression of P450 genes following neonatal exposure, which will affect drug responses in adulthood. Our current ongoing study involves administering phenytoin to neonatal mice, then evaluating expression of CYP3A11, CYP2B10, and CYP2C29, and the responses to omeprazole treatment in adulthood. Gastric pH is measured to evaluate the therapeutic efficacy of omeprazole, livers are harvested for analysis of P450 expression and activity, and blood is collected to measure plasma concentration of omeprazole and its metabolites. If phenytoin produces the same permanent upregulation of several P450s following neonatal exposure with a correlating decrease in omeprazole efficacy, then this phenomenon is not limited to phenobarbital and may be a common consequence of neonatal anti‐epileptic drug treatment. Neonates and infants are commonly administered drugs to treat various indications, such as seizures, and many of these compounds can induce P450s. This work may help prove that induction of P450s due to drug administration in early life can leave lasting alterations in the efficacy of other drugs metabolized by the P450s in later life. To better predict how patients will respond to a drug, a patient's drug history may serve as a factor for predicting variations of P450‐mediated drug metabolism.