title: Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype.
abstract: BACKGROUND
  Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites.
  
  
  METHODS
  We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy.
  
  
  RESULTS
  Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 μg/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 μg/mL) and lower N-oxide levels (1.6 vs 2.5 μg/mL).
  
  
  CONCLUSIONS
  CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Zonios
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: SAIC-Frederick Inc, National Cancer Institute at Frederick, Maryland.
authors.forename: Ven
authors.initials: V
authors.lastname: Natarajan
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Tara
authors.initials: T
authors.lastname: Palmore
authors.affiliation: National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Jeff
authors.initials: J
authors.lastname: Skinner
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: John E
authors.initials: JE
authors.lastname: Bennett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006212:Hallucinations / Q000139:chemically induced*; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: CYP2C19; metabolites; toxicity; voriconazole