Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein

A. G. Pinto, J. Horlander, N. Chalasani, M. Hamman, A. Asghar, D. Kolwankar, Stephen D. Hall

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Aims: To determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects. Methods: Intestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 μM) and NADPH for 5 min and the rate of formation of 1′-hydroxymidazolam was quantified. Results: All subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1′-hydroxymidazolam (446 pmol min-1 mg-1 6 (control) vs. 170 (CI 112, 228) pmol min -1 mg-1 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05). Conclusion: Diltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.

Original languageEnglish (US)
Pages (from-to)440-446
Number of pages7
JournalBritish Journal of Clinical Pharmacology
Volume59
Issue number4
DOIs
StatePublished - Apr 2005

Keywords

  • CYP3A
  • Diltiazem
  • Intestinal biopsy
  • Irreversible inhibition
  • Midazolam

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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