Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice

Abstract

Purpose Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU). Methods Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC–MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally. Results taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 µg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40–55% of the i.v. taTHU dose, 6–12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5–2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU. Conclusions The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.

Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC)*

“…[22] A complementary approach would be to dampen the influence of CDA altogether, by combination therapy with a CDA inhibitor such as CDAi tetrahydrouridine. [23,24] There is an active clinical trial investigation of a newer CDA inhibitor being administered concomitantly with DAC to enhance its bioavailability, whose preliminary results appear promising. [25]…”

Delineation of the Molecular Mechanisms of Nucleoside Recognition by Cytidine Deaminase through Virtual Screening

“…Tetrahydro-2'-deoxyuridine (1) [a] Also listed are the two known inhibitors tetrahydro-2'-deoxyuridine (1) and 3-deazacytidine (2), the known substrate (6), and the known inactive compound a-l-cytosine arabinoside (8), which were tested in this study as control compounds; see Table 2.…”

“…For this reason, CDA inhibitors are highly sought after as compounds to be co-administered with said drugs in order to improve their effectiveness. [6] For instance, it has been recently reported that CDA inhibition by the investigational drug zebularine enhances the antineoplastic activity of decitabine (5-aza-2′-deoxycytidine), a drug approved for the treatment of patients with myelodysplastic syndromes (MDS). [7] …”

“…For this reason, CDA inhibitors are highly sought after as compounds to be co-administered with said drugs in order to improve their effectiveness. [6] For instance, it has been recently reported that CDA inhibition by the investigational drug zebularine enhances the anti-neoplastic activity of decitabine (5-aza-2'-deoxycytidine), a drug approved for the treatment of patients with myelodysplastic syndromes (MDS). [7] Herein we describe a virtual screen for CDA ligands based on chemical similarity and molecular docking, conducted with the primary intent of shedding further light onto the structural requirements of nucleoside recognition in order to assist the future design of novel inhibitors or antitumor drugs not susceptible to deamination.…”

Formation of active products of benzaldehyde dimethane sulfonate (NSC 281612, DMS612) in human blood and plasma and their activity against renal cell carcinoma lines

“…Mice were obtained and handled in accordance with the Guide for the Care and Use of Laboratory Animals as previously described [13]. Adult female CD2F1 mice were administered a 20 mg/kg i.v.…”