title: 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 microg/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 mug/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 feasibility of using THU to decrease elimination and first-pass metabolism of cytidine analogues by CD. THU pharmacokinetics are now being evaluated in humans.
authors.affiliation: Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. beumerjh@upmc.edu
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.forename: Jeffry A
authors.initials: JA
authors.lastname: Florian
authors.forename: Erin
authors.initials: E
authors.lastname: Joseph
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: Robert S
authors.initials: RS
authors.lastname: Parker
authors.forename: Brittany
authors.initials: B
authors.lastname: Kay
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002853:Chromatography, Liquid; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D053719:Tandem Mass Spectrometry; D013767:Tetrahydrouridine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013767:Tetrahydrouridine; D003564:Cytidine Deaminase