Pharmacokinetic and pharmacodynamic study of NO-donating aspirin in F344 rats.
Nitric oxide-donating aspirin (NO-ASA) represents class of promising chemopreventive NO-NSAIDs. NO-ASA combines the beneficial effects of ASA and the gut-sparing effect of the NO moiety. There is, however, limited information on its pharmacokinetic and pharmacodynamic effects in vivo. Herein, experiments were designed to identify the optimal dose, the effective route of administration, and targeted markers in plasma and colonic tissues of male F344 rats. Seven weeks old male F344 rats were randomized into 9 groups (16/group) and fed the control diet. At eight weeks of age, groups 2-5 were each administered one of four different doses of NO-ASA by gavage (33, 66, 132 and 264 mg/kg) and each of groups 6-9 were fed diets containing NO-ASA (35, 700, 1,400 and 2,800 ppm) for two weeks. Rats were sacrificed 2 and 10 h after completion of the two weeks of treatment with NO-ASA and plasma and colonic mucosa were collected and analyzed for NO-ASA, its metabolites, and PGE2 and TXB2 levels. Our results indicate that NO-ASA is rapidly metabolized, predominantly to salicylic acid; no intact NO-ASA was detected in plasma. Compared to diet-fed NO-ASA, gavaging generated much higher salicylic acid levels over a wide range of doses and a relatively broad time period (10 h). Regardless of its route of administration, NO-ASA lowered the levels of PGE2 in colonic tissues and plasma, as well as TxB2 in plasma in a dose- and time-dependent manner. These findings may have practical utility for the administration of NO-ASA to humans.
Rao
Chinthalapally V
CV
Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Joseph
Stancy
S
Gao
Li
L
Patlolla
Jagan M R
JM
Choi
Chang-In
CI
Kopelovich
Levy
L
Steele
Vernon E
VE
Rigas
Basil
B
D000821:Animal Feed; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001241:Aspirin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D020156:Salicylic Acid / Q000378:metabolism; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D009569:Nitric Oxide; D013929:Thromboxane B2; D020156:Salicylic Acid; D001241:Aspirin