Review of fludarabine cellular pharmacology shows up to 14.5-fold exposure variability in hematological malignancy patientsDrug exposure varies wildly in patients receiving fludarabine for blood cancers

Fludarabine monophosphate is an antimetabolite and a cornerstone of hematology and oncology treatments, with expanding clinical applications in hematological malignancies, stem cell transplantation conditioning, and chimeric antigen receptor T-cell (CAR-T) therapy. Despite widespread clinical use, there is substantial interpatient pharmacokinetic variability with up to 14.5-fold differences in drug exposure. Suboptimal exposures (both under- and overexposure) correlate directly with both treatment failure and non-relapse mortality, emphasizing the critical need for personalized dosing strategies. The therapeutic efficacy of fludarabine is determined by complex transport and metabolic processes. Cellular uptake is mediated primarily by human equilibrative (hENT1, hENT2) and concentrative nucleoside transporters (hCNT2, hCNT3). Once intracellular, deoxycytidine kinase catalyzes the rate-limiting phosphorylation step, converting fludarabine to its pharmacologically active triphosphate, which inhibits DNA synthesis and repair, ultimately driving cytotoxicity. The elimination mechanisms of fludarabine involve multiple pathways: cytoplasmic 5′-nucleotidase II and CD73-mediated dephosphorylation, while UDP-glucuronosyltransferases (particularly UGT2B17) catalyze glucuronidation-based elimination. The breast cancer resistance protein (BCRP/ABCG2) represents the principal efflux transporter, whereas fludarabine shows minimal interaction with P-glycoprotein and other major multidrug resistance-associated proteins. This review synthesizes current understanding of fludarabine’s cellular pharmacology, providing a framework for identifying biomarkers to guide personalized medicine approaches and to optimize fludarabine therapy and treatment outcomes.