Drugs are commonly administered to children. With each drug or class of drugs the dose given and frequency of administration has been empirically derived or extrapolated from studies in adults. The most cited reason for different dosage requirements, unexpected toxicities, and accentuated pharmacodynamic response is that the child is """"""""immature."""""""" However, """"""""immaturity"""""""" does not explain increased dosage requirements (such as antibiotics), the increased prevalence of a side effect (anesthetic induced myocardial depression) or an increased sensitivity to drug action (narcotic suppression of respiratory drive). We seek to define the mechanisms responsible for differences in drug disposition, toxicity and action present in the developing child. Project 1 uses a metabolized antibiotic (chloramphenicol) as a prototype to define the role of metabolism in disease and age- related interpatient differences in plasma pharmacokinetics. Project 2 seeks to define the mechanism of radiosensitization of the immature brain by methotrexate: an important problem in cancer chemotherapy in children. Project 3 will document, and then define the basis of the age-related differences in morphine pharmacokinetics. With this data, the reason for the putative greater sensitivity of the infant to narcotic-induced respiratory depression will be uncovered. Project 4 tests the hypothesis that the sarcoplasmic reticular of the immature heart has a decreased ability to store calcium, and that with administration of halogenated volatile anesthetics the deficiency becomes functionally important. Project 5 tests the hypothesis that epoxide hydrolase activity is age-dependent, and that the changing activity affects carbamazepine efficacy and toxicity. This Developmental Pharmacology Center will accrue relevant and important data which will place drug administration to children on a more rational basis.
