title: CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole.
abstract: In vitro data on the metabolism of the antifungal voriconazole suggest that its pharmacokinetics might be influenced by the activity of CYP2C19, CYP2C9, and CYP3A. To elucidate the genetic influence of polymorphic enzymes on voriconazole metabolism, the authors pooled the pharmacokinetic data from 2 interaction studies in which 35 participants were enrolled according to their CYP2C19 genotype to receive a single 400-mg oral dose of voriconazole. Nine participants were homozygous for CYP2C19(*)1/(*)1, 8 heterozygous for (*)1/(*)17, 11 heterozygous for (*)1/(*)2, 2 heterozygous for (*)2/(*)17, 4 homozygous for (*)2/(*)2, and 1 with a double mutation CYP2C19(*)2/(*)2(*)17. Nine (heterozygous) individuals were carriers of the CYP2C9(*)2 or (*)3 variant alleles. Twenty-five participants did not express the CYP3A5 isozyme ((*)3/(*)3), whereas in 5 individuals, the (*)1/(*)3 combination was present (active enzyme). In addition, the CYP2D6 genotype and 2 variants of the drug transporter MDR1 (C3435T and G2677T) were determined. Multiple regression analysis of voriconazole apparent oral clearance revealed that 49% of its variance can be explained solely by the CYP2C19 polymorphism (P < .0001). Including the other polymorphisms into the regression model did not show any significant contribution. The number of variant CYP2C19 alleles therefore explains a substantial part of the wide variability of voriconazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype had no significant impact on voriconazole exposure. Some minor contribution results from the MDR1 C3435T genotype.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Magdalena Maria
authors.initials: MM
authors.lastname: Ten Hoevel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Walter-Sack
authors.forename: Michael Marcus
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D018849:Controlled Clinical Trials as Topic; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012044:Regression Analysis; D014230:Triazoles / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole