Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia

Wang, Danni; Ikemura, Kenji; Hasegawa, Tsubasa; Yamane, Fumihiro; Okuda, Masahiro

doi:https://doi.org/10.1016/j.biopha.2024.116801

Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia

Wang, Danni; Ikemura, Kenji; Hasegawa, Tsubasa et al.

Biomedicine and Pharmacotherapy, 2024, 175, 116801

Number of Access:408（2025-07-26 21:55 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97228

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Title	Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia
Creator	CreatorName Wang, Danni
	NRID 1000070513935 1000070513935 ORCID 0000-0003-1870-9571 0000-0003-1870-9571 researchmap permalink Kenji_Ikemura Kenji_Ikemura Scopus Author ID 36783115100 36783115100 CreatorName Ikemura, Kenji
	CreatorName Hasegawa, Tsubasa
	CreatorName Yamane, Fumihiro
	NRID 1000070252426 1000070252426 researchmap permalink read0042639 read0042639 Scopus Author ID 56856467300 56856467300 CreatorName Okuda, Masahiro
Subject	Human organic anion transporter 3
	Lansoprazole
	Linezolid
	PNU-142586
	Thrombocytopenia
Description	Wang D., Ikemura K., Hasegawa T., et al. Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia. Biomedicine and Pharmacotherapy 175, 116801 (2024); https://doi.org/10.1016/j.biopha.2024.116801.
Abstract	Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25–2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
Publisher	Elsevier Masson s.r.l.
Source Title	Biomedicine and Pharmacotherapy
Volume (Issue)	175
Page	116801
Date of Issued	2024-06-01
Language	English
Handle URL	https://hdl.handle.net/11094/97228
PISSN	07533322
eISSN	19506007
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.biopha.2024.116801
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Biomedicine and Pharmacotherapy. 2024, 175, p. 116801
DC.title	Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia
DC.creator	Wang, Danni
	Ikemura, Kenji
	Hasegawa, Tsubasa
	Yamane, Fumihiro
	Okuda, Masahiro
DC.publisher	Elsevier Masson s.r.l.
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-06-01
DC.identifier	https://doi.org/10.1016/j.biopha.2024.116801
DC.subject	Human organic anion transporter 3
	Lansoprazole
	Linezolid
	PNU-142586
	Thrombocytopenia
DC.description	Wang D., Ikemura K., Hasegawa T., et al. Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia. Biomedicine and Pharmacotherapy 175, 116801 (2024); https://doi.org/10.1016/j.biopha.2024.116801.
DCTERMS.abstract	Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25–2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	97228
citation_title	Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia
citation_author	Wang, Danni
	Ikemura, Kenji
	Hasegawa, Tsubasa
	Yamane, Fumihiro
	Okuda, Masahiro
citation_publisher	Elsevier Masson s.r.l.
citation_language	English
citation_date	2024-06-01
citation_journal_title	Biomedicine and Pharmacotherapy
citation_volume	175
citation_firstpage	116801
citation_doi	https://doi.org/10.1016/j.biopha.2024.116801
citation_public_url	https://hdl.handle.net/11094/97228

Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia

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