title: Evaluation of sulfonamide detoxification pathways in haematologic malignancy patients prior to intermittent trimethoprim-sulfamethoxazole prophylaxis.
abstract: OBJECTIVE
  Patients with haematologic malignancies have a reportedly high incidence of sulfamethoxazole (SMX) hypersensitivity. The objective of this study was to determine whether deficiencies in sulfonamide detoxification pathways, to include glutathione (GSH) and ascorbate (AA), and cytochrome b(5) (b5) and cytochrome b(5) reductase (b5R), were prevalent in these patients. A secondary pilot objective was to determine whether the incidence of drug hypersensitivity following intermittent trimethoprim-SMX (TMP-SMX) prophylaxis approached that reported for high dose daily regimens.
  
  
  METHODS
  Forty adult patients with haematologic malignancies (HM) and 35 healthy adults were studied; an additional 13 HM patients taking ascorbate supplements (HM-AA) were also evaluated. Twenty-two of 40 HM patients were prescribed and were compliant with TMP-SMX 960 mg three to four times weekly.
  
  
  RESULTS
  There were no significant differences between HM and healthy groups in plasma AA (median 37.2 µm vs. 33.9 µm) or red blood cell GSH (1.9 mmvs. 1.8 mm). However, plasma AA was correlated significantly with leucocyte b5/b5R reduction (r= 0.39, P= 0.002). Deficient b5/b5R activities were not found in HM patients. In fact, patients with chronic lymphocytic leukaemia or myeloma had significantly higher median activities (80.7 µmol mg(-1) min(-1)) than controls (18.9 µmol mg(-1) min(-1), P= 0.008). After 3-4 weeks of treatment, no patients developed SMX-specific T cells and only one patient developed rash.
  
  
  CONCLUSIONS
  Deficiencies of blood antioxidants and b5/b5R reduction were not found in this population with haematologic malignancies, and the development of skin rash and drug-specific T cells appeared to be uncommon with intermittent TMP-SMX prophylaxis.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706-1102, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abouraya
authors.forename: James C
authors.initials: JC
authors.lastname: Sacco
authors.forename: Brad S
authors.initials: BS
authors.lastname: Kahl
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Trepanier
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects*; D001205:Ascorbic Acid / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D042966:Cytochrome-B(5) Reductase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008875:Middle Aged; D013223:Statistics as Topic; D013420:Sulfamethoxazole / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D013449:Sulfonamides; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D042966:Cytochrome-B(5) Reductase; D005978:Glutathione; D013420:Sulfamethoxazole; D001205:Ascorbic Acid