Hans Helleberg, Inga Bjørnsdottir, Signe Beck Petersen, Hanne Kjær Offenberg
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引用次数: 0
Abstract
Decitabine (DEC) is rapidly deaminated by cytidine deaminase (CDA); tetrahydrouridine (THU), a CDA inhibitor, reduces degradation and increases DEC exposure. This is clinically relevant in sickle cell disease (SCD), where DEC increases foetal haemoglobin in erythrocytes.The effect of THU pre-treatment on the tissue distribution of radiolabelled decitabine ([14C]-DEC) was studied in mouse by quantitative whole-body autoradiography and area under the concentration curve (AUC) as exposure metric.The decitabine-related exposure was highest in haematolymphoid tissues, particularly the bone marrow, followed by gastrointestinal tissues across all dosing groups, with up to 115‑ and 18‑fold higher levels than in blood, respectively.Furthermore, THU pre-treatment increased the exposure in haematolymphoid tissues, gastrointestinal tract and reproductive organs by up to 4.8-, 6.2- and 5.3-fold, respectively.In conclusion, THU pre-treatment enhances decitabine-related exposure in target tissues like bone marrow, supporting pre-dosing of THU prior to DEC treatment of SCD.
期刊介绍：
Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology
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