title: Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily.
abstract: 1. To aid in the prediction of drug interactions with alprazolam, the human CYP involved in the 1'- and 4-hydroxylation of alprazolam were characterized using human liver microsomes, expressed enzymes and selective chemical inhibitors. 2. The formation of 4-hydroxyalprazolam and 1'-hydroxyalprazolam at an alprazolam concentration of 62.5 microM were reduced by the prototypic CYP3A inhibitor, troleandomycin (50 microM), by 97 and 9900 respectively. Only microsomes from B-lymphoblastoid cells expressing CYP3A4 were capable of catalysing the 1'- and 4-hydroxylation of alprazolam. 3. The formation rates of 1'-hydroxyalprazolam and 4-hydroxyalprazolam at an alprazolam concentration of 1 mM were significantly correlated (n = 19, r = 0.95, p<0.01) indicating that the same enzyme(s) mediated these biotransformations. A significant (p<0.01) correlation was observed between alprazolam 4- and 1'-hydroxylase activity and CYP3A-mediated midazolam 4-hydroxylase, midazolam 1'-hydroxylase, dextromethorphan N-demethylase and erythromycin N-demethylase activities. 4. In conclusion, in adult human liver the CYP3A subfamily members are the principal enzymes involved in the 1'- and 4-hydroxylation of alprazolam. Thus, clinically significant drug drug interactions between alprazolam and other CYP3A substrates are to be expected.
authors.affiliation: Department of Medicine, Indiana University, Indianapolis 46202, USA. jcgorski@iupui.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Gorski
authors.forename: D R
authors.initials: DR
authors.lastname: Jones
authors.forename: M A
authors.initials: MA
authors.lastname: Hamman
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
mesh_terms: D000525:Alprazolam / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001402:B-Lymphocytes / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D003374:Coumarins / Q000494:pharmacology; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013426:Sulfaphenazole / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D001571:Benzoflavones; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D011994:Recombinant Proteins; D013426:Sulfaphenazole; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D011802:Quinidine; D000525:Alprazolam