PI-002

J. L. Goldman, L. Van Haandel, J. Leeder; Children's Mercy Hospital, Kansas City, MO

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective antibiotic though it can cause idiosyncratic adverse drug reactions (IADRs). Bioactivation of TMP to reactive metabolites may contribute to these reactions though the extent of TMP bioactivation in vivo is unknown. Therefore, the objective of this study was to characterize TMP metabolism profiles in children tolerating drug.
METHODS: We performed a single center cross-sectional analysis of hospitalized children taking TMP-SMX as standard of care. Following consent, 25 subjects were enrolled and urine was collected during an entire TMP-SMX dosing interval at steady state. Quantification of TMP and 8 metabolites was performed by LC/MS/MS and fractional (Fr) recovery of each metabolite was calculated. Descriptive statistics were used to characterize Fr concentrations of TMP metabolites and Wilcoxon Rank Sum test was used for all comparisons.
RESULTS: On average, 95% (90-99%) of TMP was eliminated unchanged in the urine. Significant variation was appreciated among metabolite profiles. TMP-N-oxides accounted for the majority of TMP metabolism (median 86%; IQR 81-89%), while 3- and 4-desmethyl-TMP (7%; 5-10%), Cα-OH-TMP (5%; 3-8%) and N-acetyl-cysteine TMP adducts (0.03%; 0.02-0.05%) were relatively minor observed urinary metabolites. Hierarchical clustering revealed 2 apparent groups with a 3.5-fold difference in the extent of overall TMP metabolism.
CONCLUSION: Although TMP is not extensively metabolized, evidence of bioactivation was observed in every child. The relative balance of bioactivation and detoxification may provide insight into those at highest risk of developing an IADR.