Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily

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-hydroxyalpraz...

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Bibliographic Details
Published in:Xenobiotica 1999, Vol.29 (9), p.931-944
Main Authors: Gorski, J. C., Jones, D. R., Hamman, M. A., Wrighton, S. A., Hall, S. D.
Format: Article
Language:English
Subjects:
alprazolam
Alprazolam - pharmacokinetics
Aryl Hydrocarbon Hydroxylases
B-Lymphocytes - metabolism
Benzoflavones - pharmacology
Biological and medical sciences
Biotransformation
Coumarins - pharmacology
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System - drug effects
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
cytochrome P4503A
Enzyme Inhibitors - pharmacology
Humans
Hypnotics and Sedatives - pharmacokinetics
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Mixed Function Oxygenases - antagonists & inhibitors
Mixed Function Oxygenases - genetics
Mixed Function Oxygenases - metabolism
Neuropharmacology
Oxidoreductases, N-Demethylating - drug effects
Oxidoreductases, N-Demethylating - metabolism
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Quinidine - pharmacology
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Sulfaphenazole - pharmacology
Troleandomycin - pharmacology
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Summary: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 μM were reduced by the prototypic CYP3A inhibitor, troleandomycin (50 μM), by 97 and 99% 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
ISSN:0049-8254
1366-5928
DOI:10.1080/004982599238173