The JASN article titled “Ondansetron and the Risk of Sudden Cardiac Death among Individuals Receiving Maintenance Hemodialysis”1 provides a crucial exploration of treatment considerations for patients undergoing chronic hemodialysis. The authors use a comprehensive approach to validate the association, considering outcome type, ascertainment duration, indications, and the non-cancer subgroup. They propose that the heightened cardiac risk associated with ondansetron may be linked to its side effect of QT prolongation. Unexpectedly, they observe that concurrent use of other QT-prolonging medications mitigates this risk. We believe that pharmacokinetic issue may underlie this phenomenon.

In human cells, ondansetron undergoes hepatic metabolism by various cytochrome P450 forms, including CYP1A1, 1A2, 2D6, and 3A subfamily enzymes.2 As an antiemetic agent, ondansetron is frequently coprescribed with other gastrointestinal medications that may act as inducers or inhibitors of cytochrome P450 enzymes. For instance, proton pump inhibitors such as omeprazole/rabeprazole induce hepatic 1A2 expression,3 while H2 blockers such as cimetidine and ranitidine are potent CYP2D6 inhibitors. The concurrent use of other QT-prolonging medications may indicate additional coprescribed agents affecting cytochrome P450 enzyme activity, resulting in fluctuations in ondansetron serum levels and influencing end points. A Medicare database analysis reveals a significant prevalence (10.5%) of multidrug interactions involving ondansetron, higher than the overall prevalence (1.3%), with QT prolongation being a common adverse drug reaction in such cases.4 Given the increased risk of polypharmacy and drug interactions in patients undergoing chronic hemodialysis, it is essential to consider these factors.

Furthermore, cigarette smoking and exposure to environmental toxins are known inducers of CYP1A1 and 1A2, representing an additional source of potential influences on ondansetron levels. To better understand the effect of concurrent cytochrome P450 enzyme inducers or inhibitors, we recommend a more comprehensive retrieval of the medication list, extending beyond those potentially causing QT prolongation or Torsades de Pointes. Incorporating this factor into analysis will contribute to a more accurate estimation of the ondansetron-associated risk in patients undergoing chronic hemodialysis.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at https://links.lww.com/JSN/E665.

Funding

None.

Acknowledgments

We are grateful to the Second Core Laboratory, Department of Medical Research of National Taiwan University Hospital for their technical advice.

Author Contributions

Conceptualization: Chia-Ter Chao, Kuo-Chin Hung.

Data curation: Chia-Ter Chao.

Formal analysis: Chia-Ter Chao.

Funding acquisition: Chia-Ter Chao, Kuo-Chin Hung.

Investigation: Kuo-Chin Hung.

Writing – original draft: Chia-Ter Chao, Kuo-Chin Hung.

References 1. Ismail S, Funk MJ, Flythe JE. Ondansetron and the risk of sudden cardiac death among individuals receiving maintenance hemodialysis. J Am Soc Nephrol. 2024. doi:10.1681/ASN.0000000000000336 2. Dixon CM, Colthup PV, Serabjit-Singh CJ, et al. Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab Dispos 1995;23(11):1225–1230. PMID: 8591723 3. Shivanna B, Jiang W, Wang L, Couroucli XI, Moorthy B. Omeprazole attenuates hyperoxic lung injury in mice via aryl hydrocarbon receptor activation and is associated with increased expression of cytochrome P450 1A enzymes. J Pharmacol Exp Ther. 2011;339(1):106–114. doi:10.1124/jpet.111.182980 4. Anand TV, Wallace BK, Chase HS. Prevalence of potentially harmful multidrug interactions on medication lists of elderly ambulatory patients. BMC Geriatr. 2021;21(1):648. doi:10.1186/s12877-021-02594-z