AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity.
Neurotoxicity of cytarabine (AraC) is believed to be related to renal insufficiency. We examined the plasma pharmacokinetics of AraC and its deamination product uracil arabinoside (AraU) in four patients with AML and concomitant severe renal insufficiency after treatment with AraC. Additionally, in one of these patients the concentration of intracellular AraCTP, the active metabolite of AraC, was analysed. Patients 2 and 3 were treated with AraC 1.0 g/m(2) infused for 3 h at 12-h intervals on days 1-4. Patient 1 received the same schedule of AraC with 0.5 g/m(2) and patient 4 with 0.25 g/m(2) AraC. Plasma concentrations of AraC, AraU and the intracellular concentration of AraCTP were analysed at different time points using HPLC. AraC pharmacokinetics in patients with severe renal insufficiency was comparable to patients with normal renal function. Peak plasma levels as well as intracellular AraCTP kinetics were also not significantly influenced by renal dysfunction. As expected from the high dose AraC pharmacokinetic parameters, the AraU serum levels accumulated during treatment. Under the conditions of renal impairment, AraU half-life was about 75 h and the AUC was about 12-fold higher than for patients with normal renal function. AraU could be the pathophysiologic cause for the known correlation between the incidence of neurotoxicity and renal insufficiency in high-dose AraC. To avoid AraU accumulation, intermittent hemodialysis during high-dose AraC treatment could be a suitable method considering the low protein-binding and low distribution volume of AraU.
Medizinische Klinik und Poliklinik III, Klinikum Grosshadern der Universität München, Marchioninistr. 15, 81377, Munich, Germany. Lars.Lindner@med.uni-muenchen.de.
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Lindner
Medizinische Klinik und Poliklinik III, Klinikum Grosshadern der Universität München, Marchioninistr. 15, 81377, Munich, Germany.
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Ostermann
Medizinische Klinik und Poliklinik III, Klinikum Grosshadern der Universität München, Marchioninistr. 15, 81377, Munich, Germany.
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Hiddemann
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Kiani
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Würfel
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Illmer
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Karsch
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Platzbecker
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.
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Ehninger
University Hospital Carl Gustav Carus at the Technical University Dresden, Dresden, Germany.|Division Hematology and Oncology, Carl-von-Basedow Hospital Merseburg, Internal Medicine II, Merseburg, Germany.
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Schleyer
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000493:pharmacokinetics*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000139:chemically induced*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000097:blood
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D001086:Arabinofuranosyluracil