| アブストラクト | 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 IC(50) value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 +/- 0.38 microM. 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. |
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| ジャーナル名 | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie |
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| 投稿日 | 2024/5/24 |
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| 投稿者 | Wang, Danni; Ikemura, Kenji; Hasegawa, Tsubasa; Yamane, Fumihiro; Okuda, Masahiro |
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| 組織名 | Department of Hospital Pharmacy, Graduate School of Medicine, Osaka;University, Suita, Osaka 5650871, Japan.;University, Suita, Osaka 5650871, Japan; Department of Pharmacy, Osaka University;Hospital, Suita, Osaka 5650871, Japan. Electronic address:;ikemurak@hp-drug.med.osaka-u.ac.jp.;Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka;Hospital, Suita, Osaka 5650871, Japan. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/38781867/ |
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