Scientific Reports (May 2017)

Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients

  • Bora Kim,
  • Ji Won Lee,
  • Kyung Taek Hong,
  • Kyung-Sang Yu,
  • In-Jin Jang,
  • Kyung Duk Park,
  • Hee Young Shin,
  • Hyo Seop Ahn,
  • Joo-Youn Cho,
  • Hyoung Jin Kang

DOI
https://doi.org/10.1038/s41598-017-01861-7
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 11

Abstract

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Abstract Owing to its narrow therapeutic range and high pharmacokinetic variability, optimal dosing for busulfan is important to minimise overexposure-related systemic toxicity and underexposure-related graft failure. Using global metabolomics, we investigated biomarkers for predicting busulfan exposure. We analysed urine samples obtained before busulfan administration from 59 paediatric patients divided into 3 groups classified by area under the busulfan concentration-time curve (AUC), i.e., low-, medium-, and high-AUC groups. In the high-AUC group, deferoxamine metabolites were detected. Phenylacetylglutamine and two acylcarnitines were significantly lower in the high-AUC group than in the low-AUC group. Deferoxamine, an iron-chelating agent that lowers serum ferritin levels, was detected in the high-AUC group, indicating that those patients had high ferritin levels. Therefore, in a retrospective study of 130 paediatric patients, we confirmed our hypothesis that busulfan clearance (dose/AUC) and serum ferritin level has a negative correlation (r = −0.205, P = 0.019). Ferritin, acylcarnitine, and phenylacetylglutamine are associated with liver damage, including free radical formation, deregulation of hepatic mitochondrial β-oxidation, and hyperammonaemia. Our findings reveal potential biomarkers predictive of busulfan exposure and suggest that liver function may affect busulfan exposure.