Disposition and pharmacokinetics of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide, a selective iNOS inhibitor, in rats.
The metabolism, pharmacokinetics, tissue distribution, and excretion of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide (L-NIL-TA), a selective inducible NO synthase (iNOS) inhibitor, were investigated in rats. [(14)C]L-NIL-TA is extensively metabolized after either oral or IV administration with a minor amount (<1%) excreted as the prodrug. L-NIL-TA is metabolized via a single hydrolysis pathway to form the active drug, L-N6-(1-iminoethyl)lysine (L-NIL). The oxidative deamination of 2-amino group of L-NIL forms a 2-keto metabolite (M5), which further loses carbon dioxide to yield a carboxylic acid metabolite (M6). Acetylation of L-NIL and M5 resulted in the formations of metabolites M7 and M4, respectively. Complete recovery of the radioactive dose was achieved after either oral (91.2% in urine and 4.66% in feces) and IV (99.3% in urine and 5.11% in feces) administration. L-NIL-TA-related material was extensively distributed to the tissues, with the highest concentration of radioactivity being found in muscle. Maximal concentration of radioactivity was reached between 0.5 and 1 h post-dose in the majority of tissues, with the exception of muscle and skin where the maximal concentrations were achieved at 8 h post-dose.
Zhang
Ji Y
JY
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Skokie, Illinois 60077, USA. ji.y.zhang@GSK.com
Wang
Yuefen
Y
Milton
Mark N
MN
Kraus
Lori
L
Breau
Alan P
AP
Paulson
Susan K
SK
D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D000577:Amides; D004791:Enzyme Inhibitors; C487860:L-N6-(1-iminoethyl)lysine-5-tetrazole-amide; D013777:Tetrazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat