Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End-Stage Renal Disease.
ATP Binding Cassette Transporter, Subfamily B, Member 1
/ metabolism
Aged
Cytochrome P-450 CYP3A
/ metabolism
Drug Interactions
Female
Humans
Kidney
/ physiopathology
Kidney Failure, Chronic
/ diagnosis
Male
Midazolam
/ pharmacokinetics
Middle Aged
Organic Anion Transporters
/ metabolism
Prospective Studies
Renal Dialysis
Renal Elimination
Terfenadine
/ analogs & derivatives
Time Factors
Treatment Outcome
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
14
02
2020
accepted:
21
04
2020
pubmed:
2
5
2020
medline:
25
5
2021
entrez:
2
5
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 1
0
Organic Anion Transporters
0
Terfenadine
7BA5G9Y06Q
fexofenadine
E6582LOH6V
CYP3A protein, human
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Midazolam
R60L0SM5BC
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
866-873Informations de copyright
© 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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