Ontogeny of Drug Bioactivation and Idiosyncratic ADRs

Children'S Mercy Hosp (Kansas City, Mo), Kansas City MO

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Abstract

DESCRIPTION (provided by applicant): Idiosyncratic adverse drug reactions (ADRs) are relatively rare, but potentially life-threatening events in which the determinants of susceptibility (largely unknown) are thought to be unique to the individual experiencing the adverse event. They can occur throughout the age spectrum but tend to be underemphasized in the pediatric literature yet children appear to be at increased risk for certain idiosyncratic ADRs such as valproate hepatotoxicity and cutaneous reactions to lamotrigine. An important step in the development of an idiosyncratic ADR appears to be biotransformation of the implicated drug to a chemically reactive metabolite ("bioactivation") that is capable of binding to cellular macromolecules and producing cell death directly or indirectly through initiation of an immune response. Although developmental changes in drug metabolizing enzymes such as the cytochromes P450 (CYPs) and glucuronosyl transferase (UGTs) have been characterized in children, little is known about the ontogeny of drug bioactivation as children grow and develop. Using biomarkers of acetaminophen (APAP), carbamazepine (CBZ) and valproic acid (VPA) bioactivation (and detoxification) in vivo, the goals of this research program are 1. to characterize the ontogeny of the drug bioactivation biomarkers in vivo and in vitro and 2. to identify the pharmacogenetic determinants of interindividual variability in APAP, CBZ and VPA biomarker expression during growth and development. To achieve these goals, two longitudinal "bioactivation" phenotyping studies will be conducted 1. in healthy children following a single test dose of APAP (15 mg/kg as Tylenol(r) alcohol-free solution, 80mg/0.8ml) and 2. in epileptic children routinely receiving CBZ or VPA for medical management of their disease involving NICHD PPRU sites in Kansas City, MO, Shreveport, LA, and Little Rock, AR. For each study, urine is collected overnight and analyzed for the presence of parent drug, "non-toxic" metabolites and conjugated l metabolites of candidate reactive metabolites. Specific urinary metabolite ratios will be used to determine the changes in reactive metabolic "burden" that occur during growth and development with specific reference to changes in CYP activities identified in longitudinal phenotyping studies currently underway. Paired DNA samples from the extremes of the population distributions will be subjected to a concerted search by DNA sequencing and fragment analysis for single nucleotide polymorphisms (SNPs) that contribute to inter-individual variability in drug bioactivation. It is anticipated that the results of this program will allow critical periods of increased bioactivation and thus, potential vulnerability to idiosyncratic ADRs, to be identified for subsequent prospective investigations.