Effect of Levofloxacin and moxifloxacin on arsenic metabolism and cardiotoxicity in APL patients treated with arsenic trioxide
Abstract
Arsenic trioxide (ATO) is the hallmark therapy for acute promyelocytic leukemia (APL); however, its clinical utility is limited by severe cardiotoxicity. APL patients develop neutropenia and immunodeficiency due to bone marrow suppression, increasing susceptibility to community-acquired pneumonia (CAP). Levofloxacin (LFX) and moxifloxacin (MFX) serve as first-line antimicrobial agents for treating CAP in patients with APL. This study quantitatively detected plasma concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in 96 APL patients undergoing ATO therapy using HPLC-HG-AFS. LFX significantly increased the incidence of QT interval prolongation and myocardial injury, while elevating plasma arsenic concentrations in ATO-treated APL patients; in contrast, MFX showed no significant effects. In vivo studies demonstrated that LFX significantly suppressed LVEF and FS, reduced renal arsenic excretion, and increased arsenic accumulation in systemic circulation, kidneys, and hearts of ATO-treated rats, concomitant with downregulated renal P-glycoprotein (P-gp) expression; conversely, MFX exhibited none of these effects. In vitro experiments revealed that LFX suppressed P-gp expression in HEK293T cells by inhibiting the PXR/AKT/FOXO3a pathway, thereby inhibiting cellular efflux of ATO; conversely, MFX exhibited no significant effects on this regulatory axis. Collectively, our results demonstrate that LFX exacerbates ATO…
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