Modulation of Gemcitabine (2′,2′-Difluoro-2′-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine
Purpose: In vivo , 2′,2′-difluoro-2′-deoxycytidine (dFdC) is rapidly inactivated by gut and liver cytidine deaminase (CD) to 2′,2′-difluoro-2′-deoxyuridine (dFdU). Consequently, dFdC has poor oral bioavailability and is administered i.v., with associated costs and limitations in administration sched...
Saved in:
Published in | Clinical cancer research Vol. 14; no. 11; pp. 3529 - 3535 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.06.2008
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Purpose: In vivo , 2′,2′-difluoro-2′-deoxycytidine (dFdC) is rapidly inactivated by gut and liver cytidine deaminase (CD) to 2′,2′-difluoro-2′-deoxyuridine
(dFdU). Consequently, dFdC has poor oral bioavailability and is administered i.v., with associated costs and limitations in
administration schedules. 3,4,5,6-Tetrahydrouridine (THU) is a potent CD inhibitor with a 20% oral bioavailability. We investigated
the ability of THU to decrease elimination and first-pass effect by CD, thereby enabling oral dosing of dFdC.
Experimental Design: A liquid chromatography-tandem mass spectrometry assay was developed for plasma dFdC and dFdU. Mice were dosed with 100 mg/kg
dFdC i.v. or orally with or without 100 mg/kg THU i.v. or orally. At specified times between 5 and 1,440 min, mice ( n = 3) were euthanized. dFdC, dFdU, and THU concentrations were quantitated in plasma and urine.
Results: THU i.v. and orally produced concentrations >4 μg/mL for 3 and 2 h, respectively, whereas concentrations of >1 μg/mL have
been associated with near-complete inhibition of CD in vitro . THU i.v. decreased plasma dFdU concentrations but had no effect on dFdC plasma area under the plasma concentration versus
time curve after i.v. dFdC dosing. Both THU i.v. and orally substantially increased oral bioavailability of dFdC. Absorption
of dFdC orally was 59%, but only 10% passed liver and gut CD and eventually reached the systemic circulation. Coadministration
of THU orally increased dFdC oral bioavailability from 10% to 40%.
Conclusions: Coadministration of THU enables oral dosing of dFdC and warrants clinical testing. Oral dFdC treatment would be easier and
cheaper, potentially prolong dFdC exposure, and enable exploration of administration schedules considered impractical by the
i.v. route. |
---|---|
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-07-4885 |