AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity

Abstract

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.

Successful treatment of acute promyelocytic leukemia in a patient on hemodialysis

“…On the other hand, some drugs are dialyzed, so an additional dose is sometimes needed after hemodialysis. Thus, dose modification is necessary in patients with renal failure [9][10][11]. Ara-C is dialyzed and serum Ara-C level does not increase in patients with renal failure, but Ara-U (an active metabolite of Ara-C) accumulates and its halflife (t 1/2 ) becomes 12 times longer than in persons without renal dysfunction [11], so the dose of Ara-C has to be reduced.…”

“…Thus, dose modification is necessary in patients with renal failure [9][10][11]. Ara-C is dialyzed and serum Ara-C level does not increase in patients with renal failure, but Ara-U (an active metabolite of Ara-C) accumulates and its halflife (t 1/2 ) becomes 12 times longer than in persons without renal dysfunction [11], so the dose of Ara-C has to be reduced. MIT, DNR, and IDR are also excreted in the urine, but there are only a few reports about them, and their doses are usually modified empirically.…”

Management of hematological malignancies in patients affected by renal failure

“…Among antimetabolites, cytarabine [53,54,58,59], fludarabine [53][54][55]60,61,201,202], clofarabine [62], methotrexate (MTX) [26,[53][54][55]201], hydroxyurea [53], cladribrine [54,63] and pentostatin [64] require special precaution when administered in patients with RI; although potentially nephrotoxic (Table 2), no dose adjustment is recommended for the administration of azacitidine [65,66]. Cytarabine has a short halflife (15 min); its main indication is represented by AML [53,58,59].…”

“…When it is administered at high doses in patients with RI, this agent requires appropriate reduction, given that its major metabolites, such as uracil arabinoside (AraU), can accumulate during treatment, causing severe neurotoxicity [58,59]. However, given the low protein binding and low distribution volume of AraU, intermittent HD has been successfully performed to avoid the accumulation of this toxic bioproduct of cytarabine and to allow the administration of full doses of the therapeutically active parent compound [59]. Another antimetabolite that requires dose reduction in the setting of RI is fludarabine [60].…”

“…Antimetabolites Cytarabine AML (3 + 7), ALL, NHL, MDS (low doses) Yes (high doses) [54,55,58,59] Clofarabine Refractory AML, ALL Yes [62] Fludarabine CLL, NHL, AML Yes Hydroxyurea CML, IMF, AML Yes [54] Cladribrine, pentostatin HCL, CLL, NHL Yes [55,63,64] 6MP, 6TG ALL, AML No [53] 5Azacitidine MDS, AML No [65,66] Antimicrotubule agents [75] Arsenic trioxide APL, MM Yes [76,77] Asparaginase ALL No [53] ATRA APL No [78,79] Bleomycin HL, NHL Yes [54,201] Bortezomib…”