title: Obesity effects on cyclophosphamide-induced DNA damage in hematopoietic cell transplant recipients.
abstract: BACKGROUND
  Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA-DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NOR-G crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks.
  
  
  METHODS
  Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured.
  
  
  RESULTS
  Overweight/obese patients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obese patients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC(0-∞)) =529.24 vs. 867.99 μcg/ml*h respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC(0-∞)=142.8 vs. 147.0 adducts/10(6) nucleotides*h, respectively, p=0.59.
  
  
  CONCLUSIONS
  Overweight/obese patients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.
authors.affiliation: University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, 308 Harvard Street SE, 7-115C WDH, Minneapolis, MN 55443, USA. joh02745@umn.edu
authors.forename: L'Aurelle A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D006402:Hematologic Diseases / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000628:therapy; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D003520:Cyclophosphamide