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Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans.
- Source :
-
Cancer Chemotherapy & Pharmacology . Oct2015, Vol. 76 Issue 4, p803-811. 9p. - Publication Year :
- 2015
-
Abstract
- <bold>Introduction: </bold>5-Fluoro-2'-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907).<bold>Methods: </bold>Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability.<bold>Results: </bold>After IV FdCyd and THU administration, FdCyd C(max) and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %).<bold>Conclusion: </bold>Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1 to 24 %. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times three at the beginning of the first and second weeks of a 28-day cycle. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PHARMACOKINETICS
*DEOXYCYTIDINE
*LABORATORY monkeys
*DNA methylation
*CYTIDINE deaminase
*METABOLITES
*THERAPEUTICS
*ANIMAL experimentation
*ANTIMETABOLITES
*ANTINEOPLASTIC agents
*BIOAVAILABILITY
*BIOTRANSFORMATION (Metabolism)
*COMBINATION drug therapy
*CLINICAL trials
*DRUG design
*DOSE-effect relationship in pharmacology
*CLINICAL drug trials
*ENZYME inhibitors
*HYDROLASES
*INTRAVENOUS therapy
*LONGITUDINAL method
*NUCLEOSIDES
*ORAL drug administration
*PRIMATES
*RESEARCH funding
*TIME
*PILOT projects
*CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 76
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 109466247
- Full Text :
- https://doi.org/10.1007/s00280-015-2857-x