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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alprazolam / pharmacokinetics*
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Aryl Hydrocarbon Hydroxylases*
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B-Lymphocytes / metabolism
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Benzoflavones / pharmacology
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Biotransformation
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Coumarins / pharmacology
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Cytochrome P-450 CYP2C19
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / drug effects
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Enzyme Inhibitors / pharmacology
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Humans
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Hypnotics and Sedatives / pharmacokinetics*
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism*
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Mixed Function Oxygenases / antagonists & inhibitors
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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Oxidoreductases, N-Demethylating / drug effects
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Oxidoreductases, N-Demethylating / metabolism*
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Quinidine / pharmacology
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sulfaphenazole / pharmacology
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Troleandomycin / pharmacology
Substances
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Benzoflavones
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Coumarins
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Cytochrome P-450 Enzyme Inhibitors
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Enzyme Inhibitors
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Hypnotics and Sedatives
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Recombinant Proteins
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Sulfaphenazole
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alpha-naphthoflavone
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Cytochrome P-450 Enzyme System
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Troleandomycin
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Mixed Function Oxygenases
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Aryl Hydrocarbon Hydroxylases
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CYP2C19 protein, human
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CYP3A protein, human
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Cytochrome P-450 CYP2C19
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Oxidoreductases, N-Demethylating
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Quinidine
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Alprazolam