title: Cyclophosphamide-induced acute liver failure requiring transplantation in a patient with genetically deficient debrisoquine metabolism: a causal relationship?
abstract: Severe liver damage can occur after treatment with cyclophosphamide. The possible linkage to genetically deficient drug metabolic capacity is unknown. A 58-year-old woman with rheumatoid arthritis was treated with oral cyclophosphamide 50 mg twice daily for 2 months. Due to poor response the dose was doubled and liver failure requiring transplantation developed within weeks. After surgery PCR amplification using DNA from leukocytes showed that she was homozygous for the mutated allele CYP2D6B, which is predictive of the poor metaboliser phenotype for debrisoquine, occurring in 7% of Caucasians. Our patient may have accumulated high levels of the hepatotoxic 4-hydroxylated cyclophosphamide metabolite. Pharmacogenetic methods can help in exploring mechanisms of unexpected severe adverse effects.
authors.affiliation: Division of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.
authors.forename: L L
authors.initials: LL
authors.lastname: Gustafsson
authors.forename: L S
authors.initials: LS
authors.lastname: Eriksson
authors.forename: M L
authors.initials: ML
authors.lastname: Dahl
authors.forename: L
authors.initials: L
authors.lastname: Eleborg
authors.forename: B G
authors.initials: BG
authors.lastname: Ericzon
authors.forename: A
authors.initials: A
authors.lastname: Nyberg
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D003520:Cyclophosphamide / Q000009:adverse effects*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D016031:Liver Transplantation; D008875:Middle Aged
chemical_list: D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin