Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Germany NLM ID: 1256165 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1041 (Electronic) Linking ISSN: 00316970 NLM ISO Abbreviation: Eur J Clin Pharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Berlin, New York, Springer.
    • Subject Terms:
      Cytochrome P-450 CYP2C19*/genetics ; Cytochrome P-450 CYP2C19*/metabolism ; Omeprazole*/administration & dosage; Cytochrome P-450 CYP3A/metabolism ; Drug Interactions ; Fluconazole/administration & dosage ; Humans ; Midazolam/administration & dosage ; Midazolam/pharmacokinetics ; Rifampin/administration & dosage ; Sodium Bicarbonate/administration & dosage ; Yohimbine/administration & dosage
    • Abstract:
      Purpose: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine.
      Methods: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity.
      Results: Calculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266-565] to 47.2 [42.8-52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5-35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all.
      Conclusions: Microdosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used.
      Trial Registration: EudraCT: 2017-004270-34.
      (© 2022. The Author(s).)
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    • Contributed Indexing:
      Keywords: CYP2C19; Induction; Inhibition; Microdose; Omeprazole
    • Accession Number:
      2Y49VWD90Q (Yohimbine)
      8MDF5V39QO (Sodium Bicarbonate)
      8VZV102JFY (Fluconazole)
      EC 1.14.14.1 (CYP2C19 protein, human)
      EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
      EC 1.14.14.1 (Cytochrome P-450 CYP3A)
      KG60484QX9 (Omeprazole)
      R60L0SM5BC (Midazolam)
      VJT6J7R4TR (Rifampin)
    • Publication Date:
      Date Created: 20220303 Date Completed: 20220517 Latest Revision: 20220716
    • Publication Date:
      20221213
    • Accession Number:
      PMC9107402
    • Accession Number:
      10.1007/s00228-022-03304-3
    • Accession Number:
      35238961