title: Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in South American subjects.
abstract: OBJECTIVE
  The present study evaluates the acute effect of a single-dose itraconazole administration on CYP3A phenotype, as measured by cortisol MR ratio in urine.
  
  
  METHODS
  Twenty-four healthy Uruguayan subjects recruited according to strict inclusion criteria participated in an open-label, randomized, two-period, crossover study designed to evaluate the bioequivalence of an itraconazole formulation (Traconal 100 mg, Achê Labs, São Paulo, Brazil). The study comprised two treatment periods separated by a wash-out period of 14 days. In each period a series of venous blood samples were drawn over 48 hours. Three urine samples were obtained for CYP3A phenotyping: pre-dose, 24 and 48 hours after dosing. Blood and urine samples were assayed for itraconazole, beta-hydroxycortisol and cortisol using a validated chromatographic method.
  
  
  RESULTS
  The ratio of the mean AUC0-inf. T/AUC0-inf. R was included in the bioequivalence range, however, due to high variability, the CI90% was not. It was found that the cortisol metabolic ratio (MR) showed inhibition relative to basal activity in a proportion of subjects 24 hours (68 +/- 6.1%, mean +/- CI95%) and 48 hours (80 +/- 7.3%, mean +/- CI95%) after ingestion of itraconazole. A significant correlation was found between itraconazole AUC0-inf. and normalized basal CYP3A MR for the reference (r = 0.62, t = 3.72, p = 0.001) and the test product (r = 0.74, t = 5.22, p = 0.00003). A good correlation existed between basal cortisol MR and the elimination half-life of itraconazole.
  
  
  CONCLUSIONS
  The findings are in line with the hypothesis that the determination of the bioavailability of highly variable CYP3A substrates might be improved by simultaneous non-interfering phenotyping. If this is confirmed, a new methodological paradigm may need to be developed in order to take account of metabolic variability in bioequivalence evaluation of this group of drugs.
authors.affiliation: Center for Biomedical Sciences, University of Montevideo, Montevideo, Uruguay. festeve2@adinet.com.uy
authors.forename: F E
authors.initials: FE
authors.lastname: Estevez-Carrizo
authors.forename: S
authors.initials: S
authors.lastname: Ruiz
authors.forename: B
authors.initials: B
authors.lastname: Bellocq
authors.forename: C
authors.initials: C
authors.lastname: Leal
authors.forename: M T
authors.initials: MT
authors.lastname: Siri
authors.forename: M J
authors.initials: MJ
authors.lastname: del Campo
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000494:pharmacology*; D010641:Phenotype; D013810:Therapeutic Equivalency
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating