Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine.

ABSTRACT:

Background

Sickle cell disease (SCD) is caused by an inherited structural abnormality of adult hemoglobin causing polymerization. Fetal hemoglobin interferes with polymerization but is epigenetically silenced by DNA methyltransferase 1 (DNMT1) in adult erythropoiesis. Decitabine depletes DNMT1 and increases fetal and total hemoglobin in SCD patients, but is rapidly catabolized by cytidine deaminase (CDA) in vivo. Tetrahydrouridine (THU) inhibits CDA, safeguarding decitabine.

Methods

The pharmacokinetics and pharmacodynamics of three oral combination formulations of THU and decitabine, with different coatings producing different delays in decitabine release, were investigated in healthy participants.

Results

Tetrahydrouridine and decitabine were rapidly absorbed into t

SUBMITTER: Lau H 

PROVIDER: S-EPMC10524919 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature