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Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End-Stage Renal Disease.

Authors
  • Egeland, Erlend Johannessen1
  • Witczak, Bartlomiej J2
  • Zaré, Hasse Khiabani3
  • Christensen, Hege1
  • Åsberg, Anders1, 4
  • Robertsen, Ida1
  • 1 Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. , (Norway)
  • 2 Department of Nephrology, Akershus University Hospital, Lørenskog, Norway. , (Norway)
  • 3 Department of Pharmacology, Oslo University Hospital, Oslo, Norway. , (Norway)
  • 4 Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway. , (Norway)
Type
Published Article
Journal
Clinical Pharmacology & Therapeutics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Oct 01, 2020
Volume
108
Issue
4
Pages
866–873
Identifiers
DOI: 10.1002/cpt.1875
PMID: 32356565
Source
Medline
Language
English
License
Unknown

Abstract

Drug dosing is challenging in patients with end-stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P-glycoprotein (P-gp)/organic anion-transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (-3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P-gp/OATP activity. © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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