Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily

J. C. Gorski, D. R. Jones, M. A. Hamman, S. A. Wrighton, S. D. Hall

Research output: Contribution to journalArticle

68 Scopus citations

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 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 < 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.

Original languageEnglish (US)
Pages (from-to)931-944
Number of pages14
JournalXenobiotica
Volume29
Issue number9
DOIs
StatePublished - Oct 7 1999

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

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    Gorski, J. C., Jones, D. R., Hamman, M. A., Wrighton, S. A., & Hall, S. D. (1999). Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily. Xenobiotica, 29(9), 931-944. https://doi.org/10.1080/004982599238173