Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice

Abstract

Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

“…However, high rates of extrahematologic toxicities – VOD, interstitial pneumonitis and pulmonary hypertension – are observed in patients receiving this regimen [163,164]. Since both drugs are metabolized through the GSH/GST system [165], there is a strong potential for pharmacological interactions.…”

“…Bouligand et al . [164] recently found in pre-clinical studies (mice) that Bu increased the systemic plasma exposure of Mel, which was further exacerbated in iron-overloaded mice. A possible mechanism of interaction was hypothesized that involves oxidative stress and Nrf2 (nuclear factor erythroid 2–related factor 2) [164].…”

“…[164] recently found in pre-clinical studies (mice) that Bu increased the systemic plasma exposure of Mel, which was further exacerbated in iron-overloaded mice. A possible mechanism of interaction was hypothesized that involves oxidative stress and Nrf2 (nuclear factor erythroid 2–related factor 2) [164]. This intriguing body of work [163,164,166] suggests that co-TDM of Bu and Mel may prove beneficial in lessening the risk of extreme treatment-related toxicity associated with this regimen.…”

Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation

“…Chemotherapy and radiotherapy-associated hepatic damage may also contribute to the release of iron stores and diminish transferrin synthesis [22,23]. In an autologous HSCT mice model, iron overload was detected to be associated with increased melphalan and busulfan toxicities through a pharmacodynamic interaction [24]. In a recent study, the interacting effects of total body irradiation and cell transplantation on the expression of iron regulatory genes had contributed to iron overload in murine recipients [25].…”

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“…Nrf2, a cellular sensor for exogenous oxidative and toxic stress (Nguyen et al, 2009), has been known to attenuate inflammation (Kobayashi et al, 2016). Interestingly, Bouligand et al, 2016, recorded a significant elevation in GSTA1, GSTA2, and glutamate cysteine ligase catalytic subunit (GCLC) transcripts after the fifth BU injection in a mice experiment. Based on this, we hypothesize that BU activates Nrf2 transcription.…”