SYSTEMATIC REVIEW article
Front. Pharmacol.
Sec. Pharmacoepidemiology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1624044
This article is part of the Research TopicInnovations in Pharmacogenomics: Embracing Diversity and Clinical ApplicationView all 10 articles
Pharmacogenetics of metamizole-induced agranulocytosis: a systematic review and drug regulation implications
Provisionally accepted
Giovana Fernanda Santos Fidelis1
Carolina Dagli Hernandez1,2
Romina Martinelli3
Jefman Efendi Marzuki HY4,5
Baharuddin Baharuddin4
Qun-Ying Yue6
Brian Edwards7
Eder Carvalho Pincinato1
Patricia Moriel1*- 1Universidade Estadual de Campinas, Campinas, Brazil
- 2Universidade de São Paulo, São Paulo, Brazil
- 3Delta PV, Madrid, Spain
- 4Universitas Surubaya, Surubaya, Indonesia
- 5Ubaya Hospital, Surubaya, Indonesia
- 6Uppsala Monitoring Centre, Uppsala, Sweden
- 7International Society of Pharmacovigilance, Geneva, Switzerland
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This systematic review aimed to investigate the association between genetic variants and the development of metamizole-induced agranulocytosis (MIA). Additionally, the allele frequencies of the genes across different ancestry groups and the legal status of metamizole were analyzed. A literature search was conducted across nine databases for studies published up to April 08, 2025. Study selection and data extraction were performed by two independent reviewers. The Withdrawn 2.0 platform was used to assess the global legal status of metamizole, while allele frequencies were obtained from the gnomAD browser (version v4.1.0) and the Allele Frequency Net Database (AFND). Bibliometric analysis was conducted using the VOS viewer software. In total, four studies were included in the review. Data related to HLA, NAT2, CYP2C9, CYP2C19, and variants located on chromosome 9 were reported; however, statistically significant associations were observed only for variants in chromosome 9 and HLA-C*04:01. When comparing countries from different continents with varying metamizole status, the analysis of allele frequencies did not reveal sufficient differences in allele frequencies between countries, which does not justify distinct regulatory frameworks. In conclusion, this study highlights the scarcity of data in the literature reporting the association between genetic variants and MIA. Furthermore, there is insufficient evidence to justify the prohibition of metamizole in certain countries based on genetic variants alone. Additional studies are essential to evaluate the prevalence of MIA, better characterize populations, and explore potential genetic associations, particularly concerning the HLA-C*04:01 allele.
Keywords: metamizole, Dipyrone, Agranulocytosis, Pharmacogenetics, regulation
Received: 06 May 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Fidelis, Dagli Hernandez, Martinelli, Marzuki HY, Baharuddin, Yue, Edwards, Pincinato and Moriel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Patricia Moriel, Universidade Estadual de Campinas, Campinas, Brazil
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