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

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 expo...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/06cab8cab19242ea84e84676399eeb22
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spelling	oai:doaj.org-article:06cab8cab19242ea84e84676399eeb222021-12-02T15:05:17ZPharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients10.1038/s41598-017-01861-72045-2322https://doaj.org/article/06cab8cab19242ea84e84676399eeb222017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01861-7https://doaj.org/toc/2045-2322Abstract 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.Bora KimJi Won LeeKyung Taek HongKyung-Sang YuIn-Jin JangKyung Duk ParkHee Young ShinHyo Seop AhnJoo-Youn ChoHyoung Jin KangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
description	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.
format	article
author	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
author_facet	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
author_sort	Bora Kim
title	Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
title_short	Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
title_full	Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
title_fullStr	Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
title_full_unstemmed	Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
title_sort	pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/06cab8cab19242ea84e84676399eeb22
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Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients

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