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.
Subject(s)
Prodrugs/pharmacokinetics , Tetrahydrouridine/analogs & derivatives , Tetrahydrouridine/pharmacokinetics , Administration, Oral , Animals , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/pharmacokinetics , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/urine , Area Under Curve , Biocatalysis/drug effects , Biological Availability , Blood/metabolism , Cytidine Deaminase/antagonists & inhibitors , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/metabolism , Humans , Injections, Intravenous , Male , Mice , Mice, Inbred Strains , Models, Biological , Prodrugs/metabolism , Prodrugs/pharmacology , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Specific Pathogen-Free Organisms , Tetrahydrouridine/blood , Tetrahydrouridine/metabolism , Tetrahydrouridine/pharmacology , Tetrahydrouridine/urine , Urine/chemistry , GemcitabineABSTRACT
2-14C-tetrahydrouridine was prepared and used to determine the serum levels and excretion of tetrahydrouridine by varous experimental animals. In mice injected ip with the agent (50 mg/kg), the serum level of tetrahydrouridine was maximum (76 mug/ml) at 15 minutes. For rats injected with the same dose, the tetrahydrouridine content of serum was greatest (58 mug/ml) at 30 minutes. Within 3 hours, the serum content of the drug in both mice and rats fell to less than 10% of the maximum. The kidneys of mice selectively accumulated tetrahydrouridine; the concentration rose to 275 mug/g at 1 hour after injection. Nearly all of the dose was excreted unchanged in the urine of mice and rats in 24 hours. For a dog and a monkey given an iv dose (50 mg/kg) of tetrahydrouridine, serum levels of the agent were 210 and 200 mug/ml, respectively, at 5 minutes. The apparent half-lives for the initial phase of disappearance were 18 and 20 minutes and those for the later phase were 65 and 70 minutes, respectively. In 24 hours the dog and monkey excreted most of the dose as unchanged tetrahydrouridine. No metabolites were detected in the biologic samples from either species.
