A major therapeutic challenge of modern medicine is the ever-increasing incidence of asthma in children during the past several decades. However, one significant therapeutic modality that has provided considerable progress is the use of inhaled glucocorticoids (GC) that target the inflammatory component of asthma while minimizing systemic GC adverse effects. These drugs provide considerable reduction in mortality and in incidence and severity of asthma symptoms, but estimates of resistance to GCs are as high as 50% of the pediatric asthmatic population. As much as 90% of inhaled GCs are swallowed and absorbed, but systemic effects are minimized through first pass hepatic metabolism. Presumably, inhaled GCs act locally within the lung where their concentrations are highest and are then metabolized by cytochrome P450 enzymes in situ. The three major CYP3A enzymes (3A4, 3A5, 3A7) are the primary catalysts of GC oxidation in human liver, where much is known about the ontogeny and developmental expression of the enzymes. However, essentially nothing is known about the relative levels of CYP3A expression in lungs of children, or the developmental changes during childhood in the important respiratory cells where GC drugs act and undergo oxidative metabolism. The exact chemical pathways catalyzed by the CYP 3A enzymes in the metabolism of GCs are also not known. Genetic polymorphisms, organ-selective expression, and autoinduction of the CYP3A genes are known mechanisms that predict dramatic interindividual metabolic diversity, resulting in resistance or hypersensitivity to GCs. None of these processes has been studied in asthmatic children. The major long-term goal of this research is to significantly improve GC therapy in asthmatic children, and the hypothesis of this application is resistance or hypersensitivity to inhaled GCs in pediatric asthmatics is predominantly controlled by developmental expression patterns, genetic polymorphisms, and environmental responsiveness of P450 3A genes. We will address this hypothesis with the following specific aims: 1) characterize the metabolites and metabolic pathways of the five most frequently used, therapeutically relevant GCs by each of the three major CYP3A enzymes;2) evaluate the induction of the 3A genes in lung and liver cells;3) correlate GC-induced P450 3A transcripts to increased metabolism of the steroids and establish developmental patterns of P450 3A gene expression in pediatric pulmonary cells from tracheal suctioning samples;and 4) correlate CYP3A5 and CYP3A7 polymorphisms with GC resistance or hypersensitivity from a cohort of pediatric asthma patients. The results of this experimental plan will provide essential information on the basic genetic and biochemical factors that lead to effective GC therapy. This knowledge can be used with genotype analysis to guide the clinical choice of GC products, and provide a more robust rationale for alternative asthmatic treatment modalities.
Inhaled glucocorticoid medicines (GC) provide effective therapy for children with asthma, but as many as 50% of children with asthma are not helped by inhaled GCs, i.e. they are resistant to these medicines. Essentially nothing is known about the relative levels of P450 enzyme expression in lungs of children, or the developmental changes during childhood in the important respiratory cells where GC agents act and are cleared. The major long-term goal of this research is to significantly improve GC therapy in asthmatic children.
|Roberts, Jessica K; Stockmann, Chris; Constance, Jonathan E et al. (2014) Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin Pharmacokinet 53:581-610|
|Ward, Robert M; Allegaert, Karel; de Groot, Ronald et al. (2014) Commentary: Continuous infusion of vancomycin in neonates: to use or not to use remains the question. Pediatr Infect Dis J 33:606-7|
|Stockmann, Chris; Ross, Joseph S; Sherwin, Catherine M T et al. (2014) Rate of asthma trial outcomes reporting on ClinicalTrials.gov and in the published literature. J Allergy Clin Immunol 134:1443-6|
|Stockmann, Chris; Fassl, Bernhard; Gaedigk, Roger et al. (2013) Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control. J Pediatr 162:1222-7, 1227.e1-2|
|Roberts, Jessica K; Moore, Chad D; Ward, Robert M et al. (2013) Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes. J Pharmacol Exp Ther 345:308-16|
|Moore, Chad D; Roberts, Jessica K; Orton, Christopher R et al. (2013) Metabolic pathways of inhaled glucocorticoids by the CYP3A enzymes. Drug Metab Dispos 41:379-89|
|Doby, Elizabeth H; Benjamin Jr, Daniel K; Blaschke, Anne J et al. (2012) Therapeutic monitoring of voriconazole in children less than three years of age: a case report and summary of voriconazole concentrations for ten children. Pediatr Infect Dis J 31:632-5|
|Murai, Takahiro; Reilly, Christopher A; Ward, Robert M et al. (2010) The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 enzyme. Chem Res Toxicol 23:1356-64|
|Moore, Chad D; Shahrokh, Kiumars; Sontum, Stephen F et al. (2010) Improved cytochrome P450 3A4 molecular models accurately predict the Phe215 requirement for raloxifene dehydrogenation selectivity. Biochemistry 49:9011-9|