title: Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.
abstract: OBJECTIVE
  Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19.
  
  
  METHODS
  In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis.
  
  
  RESULTS
  When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26%+/-16% (P > .05) lower in CYP2C19*1/*2 individuals and 66%+/-14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354+/-173 mL/min versus 202+/-139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism.
  
  
  CONCLUSIONS
  Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. gerd.mikus@med.uni-heidelberg.de
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Verena
authors.initials: V
authors.lastname: Schöwel
authors.forename: Magdalena
authors.initials: M
authors.lastname: Drzewinska
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ding
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Torben
authors.initials: T
authors.lastname: Thomsen
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000009:adverse effects*; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole
chemical_list: D019380:Anti-HIV Agents; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole; D019438:Ritonavir