Pharmacokinetics and Toxicity of Dimethylacetamide and Its Metabolite in Pediatric Patients Treated With High Dose Intravenous Busulphan

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Abstract
N,N‐dimethylacetamide (DMA) is an organic solvent, used in busulphan, iv‐formulation, (Busulfex). DMA is metabolized primarily to N‐methylacetamide (MMA) via CYP2E1. In the present study, we investigated the pharmacokinetics and toxicity of DMA and MMA in patients, mice and cell lines. In pediatric patients (6 months to 18 years) undergoing hematopoietic stem cell transplantation, the pharmacokinetics of DMA and MMA were followed during the 4‐days Busulfex conditioning (3.2–4 mg/kg, b.i.d). No accumulation of DMA was found; however, a significant increase in clearance and a significant decrease ( p < 0.005) in half‐lives by the end of treatment were observed which might indicate CYP2E1 autoinduction. Furthermore, continuous increases in plasma concentration of MMA were observed during treatment and a terminal half‐life of 15.2 ± 1.7 h was detected. Moreover, ALT was significantly ( p = 0.04) increased in > 61% of the patients after conditioning. Additionally, mice were treated with either dimethyl sulfoxide (DMSO), DMA, busulphan in DMSO, Busulfex or saline for 4 days. DMA‐treated mice showed elevated ALT and AST values. Interestingly, Busulfex administration did not alter mice liver enzymes. Busulphan in DMA showed higher cytotoxicity compared to busulphan in DMSO in HepG‐2, Huh‐7 and HL‐60 cells. The combination Bu‐DMA‐MMA exhibited increased cytotoxicity in a concentration‐dependent manner. In conclusion, Busulfex administration to pediatric patients resulted in an accumulation of MMA during the 4‐days treatment. Busulfex is less toxic compared to Bu dissolved in DMA. MMA addition to Bu in DMA showed higher cytotoxicity. Therefore, MMA with a relatively long half‐life may induce hepatotoxicity and/or interaction with subsequently administered drugs; thus further investigations are urgently warranted.

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