Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice

Abstract

Cytidine analogues such as cytosine arabinoside, gemcitabine, decitabine, 5-azacytidine, 5-fluoro-2′-deoxycytidine and 5-chloro-2′-deoxycytidine undergo rapid catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU) is a potent CD inhibitor that has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU pharmacokinetics has not been fully characterized, which has impaired the optimal preclinical evaluation and clinical use of THU. Therefore, we characterized the THU pharmacokinetics and bioavailability in mice. Mice were dosed with THU iv (100 mg/kg) or po (30, 100, or 300 mg/kg). Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma pharmacokinetic parameters were calculated compartmentally and non-compartmentally. THU, at 100 mg/kg iv had a 73 min terminal half-life and produced plasma THU concentrations >1 μg/ml, the concentration shown to effectively block deamination, for 4 h. Clearance was 9.1 ml/min/kg, and the distribution volume was 0.95 l/kg. Renal excretion accounted for 36-55% of the THU dose. A three-compartment model fit the iv THU data best. THU, at 100 mg/kg po, produced a concentration versus time profile with a plateau of approximately 10 μg/ml from 0.5-3 h, followed by a decline with an 85 min half-life. The oral bioavailability of THU was approximately 20%. The 20% oral bioavailability of THU is sufficient to produce and sustain, for several hours, plasma concentrations that inhibit CD. This suggests the NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript feasibility of using THU to decrease elimination and first-pass metabolism of cytidine analogues by CD. THU pharmacokinetics are now being evaluated in humans.

Modulation of Gemcitabine (2′,2′-Difluoro-2′-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine

“…The pharmacokinetics of THU in this study were very similar to our earlier findings when investigating the pharmacokinetics and oral bioavailability of THU in mice (18). At a first glance, the coadministration of oral dFdC 30 min after oral THU seemed to reduce the absorption of THU from the gut.…”

“…2C also contains the plasma concentration versus time profile of THU dosed alone i.v. or orally, as described earlier (18). Pharmacokinetic variables calculated noncompartmentally are displayed in Table 2.…”

“…bioavailability of THU in mice is sufficient to produce THU plasma concentrations that fully inhibit CD (18), and we have shown that oral THU increases plasma exposure to FdCyd in mice 58-fold (15), a finding that has resulted in initiation of investigations into the oral dosing of FdCyd and THU in humans. Administering dFdC orally would enable easier and cheaper treatment of patients, and it would allow exploration of administration schedules currently considered impractical.…”

“…(formulated together), (d) dFdC orally 30 min after THU orally, and (e) dFdC orally and THU i.v. The rationale for separate dosing of THU orally 30 min before dFdC orally is the T max of THU orally of 30 min observed previously (18). The vehicle consisted of 5% dextrose (Baxter).…”

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…To investigate whether increasing chemotherapy concentrations alone is sufficient to elicit improved response rates, we used the CDA inhibitor 3,4,5,6-tetrahydrouridine (THU) (31,32) to decrease the degradation and elimination of gemcitabine. Gemcitabine and THU were coadministered in tumor-bearing KPC mice, followed by the analysis of gemcitabine metabolites in plasma and PDA tumor biopsies.…”