Drug-drug interactions cytochrome P-450 enzyme system decitabine membrane transport proteins tetrahydrouridine

Journal

Xenobiotica; the fate of foreign compounds in biological systems
ISSN: 1366-5928
Titre abrégé: Xenobiotica
Pays: England
ID NLM: 1306665

Informations de publication

Date de publication:
Jan 2022
Historique:
pubmed: 17 12 2021
medline: 17 3 2022
entrez: 16 12 2021
Statut: ppublish

Résumé

1. NDec is a novel, oral, fixed-dose formulation of decitabine and tetrahydrouridine that is currently being developed for the treatment of patients with sickle cell disease. Here, we examine the potential for both components of NDec to interact with key drug metabolising enzymes (tetrahydrouridine only) and drug transporters (decitabine and tetrahydrouridine).2. This study assessed the inhibition and induction of cytochrome P450 (CYP) enzymes by tetrahydrouridine, as well as the involvement of specific drug metabolising enzymes in tetrahydrouridine metabolism. Inhibition of efflux and uptake transporters by both decitabine and tetrahydrouridine was also studied.3. Tetrahydrouridine did not inhibit or induce relevant CYP enzymes at concentrations ranging from 0.1 to 100 μM. Metabolism of tetrahydrouridine did not occur in the presence of the human drug metabolising enzymes tested. Tetrahydrouridine showed weak inhibition towards the MATE2-K transporter (∼30% inhibition at 5 and 50 μM), which was not deemed clinically relevant. Tetrahydrouridine did not inhibit any of the remaining uptake or efflux transporters. Decitabine (0.5 and 5 μM) did not inhibit any of the evaluated uptake or efflux drug transporters.4. Data presented confirm that tetrahydrouridine and decitabine are unlikely to be involved in metabolism- or transporter-based drug-drug interactions.

Identifiants

pubmed: 34913834
doi: 10.1080/00498254.2021.2018628
doi:

Substances chimiques

Membrane Transport Proteins 0
Tetrahydrouridine 18771-50-1
Decitabine 776B62CQ27

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1-15

Auteurs

Carolina Säll (C)

Development ADME, Novo Nordisk A/S, Måløv, Denmark.

Christian Fogt Hjorth (C)

Development ADME, Novo Nordisk A/S, Måløv, Denmark.

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Classifications MeSH