title: N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation.
abstract: Busulfan is currently used as a main component in the conditioning regimen prior to allogeneic stem cell transplantation (SCT). Several studies have shown a correlation between exposure to busulfan and transplantation-related liver toxicity, such as venoocclusive disease (VOD) in patients undergoing SCT. Busulfan is metabolized mainly through glutathione (GSH). During high-dose therapy, busulfan may deplete hepatocellular levels of GSH. As part of the conditioning therapy, busulfan is usually followed by high doses of cyclophosphamide. The activation of cyclophosphamide yields a cytotoxic metabolite, 4-hydroxy cyclophosphamide, which is highly reactive and detoxified through GSH. According to recent studies using cell lines and animal models N-acetyl-L-cysteine (NAC), a GSH precursor, does not hamper the myeloablative effect of busulfan during conditioning. In the present study, we administered NAC during conditioning to 10 patients at risk of VOD due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC infusions were observed and busulfan concentrations were not affected. All patients became pancytopenic and engrafted with 100% donor cells. None of the patients developed VOD or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggest that NAC therapy is safe and does not impair the myeloablative effect of busulfan during conditioning prior to SCT.
authors.affiliation: Center for Allogeneic Stem Cell Transplantation, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Sjöö
authors.forename: J
authors.initials: J
authors.lastname: Aschan
authors.forename: L
authors.initials: L
authors.lastname: Barkholt
authors.forename: Z
authors.initials: Z
authors.lastname: Hassan
authors.forename: O
authors.initials: O
authors.lastname: Ringdén
authors.forename: M
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D001663:Bilirubin / Q000494:pharmacology; D002066:Busulfan / Q000097:blood / Q000494:pharmacology*; D002648:Child; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation / Q000379:methods*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D002066:Busulfan; D005978:Glutathione; D001663:Bilirubin; D000111:Acetylcysteine