Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of approximately 25% of drugs used clinically several of which are commonly used in children of various ages. The CYP2D6 gene has several variant forms that are associated with no activity or reduced activity compared to the """"""""normal"""""""" version of the gene. While genetic testing for CYP2D6 is becoming more accessible, guiding drug therapy with genetic information alone may not be sufficient in children as the genotype-phenotype relationship may be influenced by developmental changes that occur between birth and adolescence. The purpose of this proposal is to investigate the relative roles of ontogeny and genetic variation in the observed variability in CYP2D6 activity in school- aged children and adolescents, and to assess the functional consequences of the observed variability. To achieve these goals, a total of 180 children and adolescents from 6 to 15 years of age, consisting of patients with a primary diagnosis of attention deficit-hyperactivity disorder (ADHD;n=60) and age- and sex-matched controls (n=120), will have their CYP2D6 activity measured every 6 months for 3 years (Aim 1). The activity measurement will utilize the over- the-counter cough suppressant, dextromethorphan or """"""""DM"""""""", a standard probe for determining CYP2D6 phenotype. The procedure involves administering a 0.5 mg/kg dose of DM and collecting urine over the following four hours. CYP2D6 activity or """"""""metabolizer"""""""" status is assigned based on the relative amounts of DM and the metabolite produced by CYP2D6, dextrorphan (DX), present in the urine sample.
Aim 2 will test the hypothesis that CYP2D6 poor metabolizers can be distinguished from extensive metabolizers based on a metabolomic biomarker pattern present in urine samples collected for Aim 1. In the study for Aim 3, the DM to be used will contain a stable isotope of carbon ([13C]) to determine if a rapid, office-based assessment of CYP2D6 is feasible. The principle of this test is that the [13C]-methyl group released by CYP2D6-mediated O-demethylation of [13C]-dextromethorphan appears in expired air as [13C]O2, referred to as a 'breath test'. Finally, the functional consequences of CYP2D6 activity (Aim 4) will be assessed by comparing the systemic exposure to the non-stimulant drug atomoxetine (Strattera(R)) in two groups of ADHD extensive metabolizers drawn from the highest and lowest 20th percentiles of the breath test data distribution. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients.
Cytochrome P450 2D6 (CYP2D6) is an important enzyme in the body for breaking down many medications that are commonly used in children of various ages. The purpose of this proposal is to investigate the relative roles of development and genetic variation in CYP2D6 activity in school-aged children and adolescents using the over-the-counter cough suppressant, dextromethorphan or """"""""DM"""""""", a standard probe for determining CYP2D6 phenotype. Embedded in the study design are sub-studies to investigate the potential of a DM breath test to serve as a rapid test of CYP2D6 activity that may be performed in doctors'offices as well as a search for normal body by-products that reflect differences in enzyme activity. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients.
|Brown, J T; Abdel-Rahman, S M; van Haandel, L et al. (2016) Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD. Clin Pharmacol Ther 99:642-50|
|Tracy, Timothy S; Chaudhry, Amarjit S; Prasad, Bhagwat et al. (2016) Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism. Drug Metab Dispos 44:343-51|
|Gaedigk, Andrea; Riffel, Amanda K; Leeder, J Steven (2015) CYP2D6 Haplotype Determination Using Long Range Allele-Specific Amplification: Resolution of a Complex Genotype and a Discordant Genotype Involving the CYP2D6*59 Allele. J Mol Diagn 17:740-8|
|Gaedigk, Andrea; Freeman, Natalie; Hartshorne, Toinette et al. (2015) SNP genotyping using TaqMan technology: the CYP2D6*17 assay conundrum. Sci Rep 5:9257|
|Crews, K R; Gaedigk, A; Dunnenberger, H M et al. (2014) Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95:376-82|
|Wang, Danxin; Poi, Ming J; Sun, Xiaochun et al. (2014) Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Hum Mol Genet 23:268-78|
|Leeder, J S; Brown, J T; Soden, S E (2014) Individualizing the use of medications in children: making Goldilocks happy. Clin Pharmacol Ther 96:304-6|
|Tay-Sontheimer, Jessica; Shireman, Laura M; Beyer, Richard P et al. (2014) Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. Pharmacogenomics 15:1947-62|
|McWilliam, Stephen J; Antoine, Daniel J; Sabbisetti, Venkata et al. (2014) Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children. Biomark Med 8:1189-97|
|Goldman, Jennifer; Becker, Mara L; Jones, Bridgette et al. (2011) Development of biomarkers to optimize pediatric patient management: what makes children different? Biomark Med 5:781-94|