Comparative study on the occurrence of adverse effects in the concomitant use of azathioprine and aldehyde oxidase inhibitors

ABSTRACT

Objectives

Aldehyde oxidase (AO) is a molybdenum-containing redox enzyme similar to xanthine oxidase that is involved in the thiopurine metabolism. This study investigated the effects of drug-drug interactions (DDIs) between azathioprine (AZA) and AO inhibitors on hematologic and hepatic disorders using the U.S. Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report database.

Methods

The presence of DDI was assessed using the interaction signal scores (ISSs) calculated via the reporting odds ratios and 95% confidence intervals. The study used reports of ‘azathioprine’ as a suspect drug for adverse effects. AO inhibitors were selected based on previous in vitro reports.

Results

Some drugs tested positive for ISSs in each database and type of adverse effect (hematologic or hepatic disorder) analysis. Among these drugs, chlorpromazine, clozapine, hydralazine, and quetiapine could inhibit AZA metabolism via AO, given the previously reported clinical blood concentration and inhibitory effects of each drug.

Conclusion

Concomitant use of AO inhibitors increased the signals for AZA-induced adverse effects. To date, no studies have evaluated the clinical importance of AO as a drug-metabolizing enzyme, and further in vitro and clinical research is needed to clarify the contribution of AO to the pharmacokinetics of thiopurines.

KEYWORDS:

• Aldehyde oxidase
• azathioprine
• FAERS
• JADER
• hematologic disorders
• data mining signal detection

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We would like to thank Editage (http://www.editage.jp) for the English language editing.

Ethics statement

Not applicable because spontaneous reports of the FAERS and JADER are anonymous and public.

Author contributions

HU, KN and MK designed the study. HU and SA performed data curation and formal analyses. All authors contributed to the data interpretation. HU drafted the manuscript. KN supervised the study. All authors contributed to the critical revision of the manuscript for important intellectual content.

Data availability statement

The datasets generated and/or analyzed during the current study are available in the FAERS (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html) and JADER (https://www.info.pmda.go.jp/fukusayoudb/CsvDownload.jsp) repositories.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2295976

Additional information

Funding

This work was supported in part by Grants-in-Aid from the Japan Society for the Promotion of Science Research [grant number 23KJ003903 to HU] and KAKENHI [grant number JP23K06229 to KN].