title: Unusually low clearance of two CYP3A substrates, alprazolam and trazodone, in a volunteer subject with wild-type CYP3A4 promoter region.
abstract: A healthy 40-year-old Caucasian male volunteer displayed unusually low clearance and long elimination half-life of alprazolam and trazodone, two CYP3A substrate drugs, following single-dose oral administration in clinical pharmacokinetic studies. Genomic DNA isolated from the individual's peripheral blood was subjected to polymerase chain reaction amplification and subsequent sequence analysis of a 592 base-pair segment upstream from the CYP3A coding region. The analysis revealed no variation from wild-type in the nucleotide present at position -290, previously suggested to influence expression and/or activity of CYP3A. The functional significance of this promoter region mutation is unclear and requires further evaluation.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: T H
authors.initials: TH
authors.lastname: Tran
authors.forename: M M
authors.initials: MM
authors.lastname: Cotreau
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
mesh_terms: D000328:Adult; D000525:Alprazolam / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014196:Trazodone / Q000493:pharmacokinetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014196:Trazodone; D000525:Alprazolam