Ontogeny and pharmacogenetics: determinants of age-associated differences in drug clearance during human development
Development per se represents a continuum of biologic events that enable adaptation, somatic growth and eventually, reproduction. From a societal, psychosocial, behavioral and medical perspective, it is generally appreciated that infants and children are far different from adults and elderly. As well, pediatric patients suffer from conditions and diseases that in many instances are unique and have no true counterpart in adults. These particular differences are generally known and to a great degree, determine how infants, children and adolescents are provided for both within the context of medical care and in society. What remains often under-appreciated is the fact that development exerts profound influences on pediatric pharmacotherapy. Specifically, normal human development is a dynamic process, especially during the first five years of life, with changes in organ structure and function that can dramatically impact upon drug disposition and action. Unlike the different sizes of infants and children that are readily apparent from visual inspection, the impact of ontogeny on pharmacokinetics and pharmacodynamics of therapeutic drugs and other xenobiotics is often not apparent. The basic and translational science investigations that constitute this thesis were performed specifically to examine the impact of ontogeny on the activity of important drug metabolizing enzymes. This was accomplished using "traditional" approaches (e.g., examining the pharmacokinetics of a specific drug known to be a substrate for a specific enzyme as a function of age), by developing new techniques with enhanced specificity suitable for use across the pediatric age spectrum (e.g., characterization of cisapride as a selective CYP3A4 probe) and by demonstrating how integration of the "new biology" (e.g., incorporation of relevant pharmacogenomics) into pediatric clinical pharmacology investigations can be used as a "tool" to examine how much of the variability observed in pediatric pharmacokinetic data is associated with development vs. normal, genetically determined interindividual variability in the activity of a drug metabolizing enzyme.
|Keywords||children, ontogeny, pharmaceutics, pharmacokynetics|
|Promotor||Tibboel, D. (Dick) , Anker, J.N. van den (John)|
|Publisher||Erasmus MC: University Medical Center Rotterdam|
Kearns, G.L.. (2002, October 23). Ontogeny and pharmacogenetics: determinants of age-associated differences in drug clearance during human development. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/32017