In a recent publication, Zheng and colleagues report on a potential mechanism for the metabolic activation of deferiprone by CYP2A6 (Zheng et al. Citation2021). While the mechanism described may benefit the scientific community’s understanding of deferiprone metabolism, we challenge the authors’ proposal that this mechanism is a potential means for ‘better understanding the mechanisms of the reported deferiprone-induced liver injury.’
Chiefly, we find an issue with the authors’ premise for the manuscript that ‘long-term use of deferiprone has been shown to cause liver injury (Maggio et al. Citation2002; Cohen et al. Citation2003)’ and their claim that ‘Recently, many cases of liver damage caused by deferiprone have been reported (Ceci et al. Citation2002; Xie et al. Citation2016), neither of which are supported by the cited references. Ceci et al., who examined the safety and effectiveness of treatment with deferiprone for up to three years in patients with thalassaemia, found that alanine aminotransferase (ALT) transiently increased in some patients, but no significant changes in ALT were observed after 24 months of therapy. The authors state that ‘these results are consistent with previous studies in which ALT increases were transient and occurred mainly in patients seropositive for hepatitis C’ (Ceci et al. Citation2002).
While elevated liver enzymes were seen in clinical trials of deferiprone in patients with thalassaemia, these elevations were usually transient, usually seen in patients who were hepatitis C-positive, and were not associated with an increase in liver fibrosis scores (Maggio et al. Citation2002; Wanless et al. Citation2002). Similarly, in paediatric populations, the elevations in ALT seen upon treatment with deferiprone were minor and transient (Elalfy et al. Citation2010; Elalfy et al. Citation2018). A long-term study of the safety and efficacy of deferiprone in patients with thalassaemia major reported a trend analysis showing no significant change in ALT levels over a 4-year treatment period, regardless of hepatitis C status, and observed that the percentage of patients with ALT levels greater than twice the upper limit of normal did not differ between baseline and after 48 months of deferiprone treatment (Cohen et al. Citation2003). More recently, a 5-year trial comparing deferiprone to deferoxamine in patients with thalassaemia intermedia reported that in the 47 patients treated with deferiprone, increases in ALT levels were slight and were not followed by other biochemical liver findings (Calvaruso et al. Citation2015).
The authors do provide evidence for the possible generation of an o-quinone intermediate metabolite of deferiprone. However, when they propose this metabolite may react with nucleophilic liver proteins, causing liver damage, they neglect to provide any evidence that such an interaction is happening, and, indeed, found no significant cytotoxicity in rat primary hepatocytes upon incubation with high concentrations of deferiprone. This result, combined with the authors’ unsubstantiated premise, as refuted by the clinical evidence described above, calls into question their conclusion that this metabolite may contribute to deferiprone-induced liver injury.
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The author is an employee of Chiesi Canada Corp.
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References
- Calvaruso G, Vitrano A, Di Maggio R, Lai E, Colletta G, Quota A, Gerardi C, Rigoli LC, Sacco M, Pitrolo L, et al. 2015. Deferiprone versus deferoxamine in thalassemia intermedia: results from a 5-year long-term Italian multicenter randomized clinical trial. Am J Hematol. 90(7):634–638.
- Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, Galanello R, Maggio A, Masera G, Piga A, et al. 2002. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol. 118(1):330–336.
- Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. 2003. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood. 102(5):1583–1587.
- Elalfy MS, Adly A, Awad H, Tarif Salam M, Berdoukas V, Tricta F. 2018. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: a randomized controlled trial. Am J Hematol. 93(2):262–268.
- Elalfy MS, Sari TT, Lee CL, Tricta F, El-Beshlawy A. 2010. The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload. J Pediatr Hematol Oncol. 32(8):601–605.
- Maggio A, D’Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, Di Gregorio F, Garozzo G, Malizia R, Magnano C, et al. 2002. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis. 28(2):196–208.
- Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, Schwartz E, Cohen AR. 2002. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood. 100(5):1566–1569.
- Xie Y-Y, Lu Z, Kong X-L, Zhou T, Bansal S, Hider R. 2016. Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones- Attempted optimization of the orally active iron chelator, deferiprone. Eur J Med Chem. 115:132–140.
- Zheng X, Wang X, Ding Z, Li W, Peng Y, Zheng J. 2021. Metabolic activation of deferiprone mediated by CYP2A6. Xenobiotica. 1–33.