Plasma pharmacokinetics of a liver-selective nitric oxide-donating diazeniumdiolate in the male C57BL/6 mouse.
1. The single-dose plasma pharmacokinetics of O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) following intravenous (i.v.) and intraperitoneal (i.p.) bolus administration to the male C57BL/6 mouse was studied in an effort to characterize the disposition of the agent and to serve as a basis for the design of in vivo efficacy studies. 2. Plasma V-PYRRO/NO concentrations declined rapidly in a bi-exponential manner after i.v. administration of 5 mg kg(-1) body weight to mouse. The terminal half-life was 9.4 min and the mean residence time was 3.4 min. 3. V-PYRRO/NO was absorbed rapidly following i.p. administration, with peak plasma concentrations being observed 3 min after injection. Levels then declined with a terminal half-life of 11.7 min. The bioavailable fraction from the i.p. compartment was 19%, indicating a high first-pass effect. 4. The results provide additional evidence for a liver-selective metabolism of this nitric oxide-donating prodrug.
Stinson
S F
SF
Developmental Therapeutics Program, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 20702-1201, USA. stinson@dtpax2.ncifcrf.gov
House
T
T
Bramhall
C
C
Saavedra
J E
JE
Keefer
L K
LK
Nims
R W
RW
D000818:Animals; D001391:Azo Compounds / Q000097:blood* / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply* / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D011759:Pyrrolidines / Q000008:administration & dosage
D001391:Azo Compounds; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; C452539:diazeniumdiolate; D009569:Nitric Oxide