Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog.
1. The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog. 2. The dose of [14C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5 mg kg-1), with Cmax of radioactivity of 6.45-7.07 microg equivalents g-1 occurring at 0.33-0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively. 3. Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [14C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%. 4. Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.
Zhang
J Y
JY
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Skokie, IL, USA. ji.y.zhang@gsk.com
Wang
Y F
YF
Milton
M N
MN
Beconi
M
M
Chang
M
M
Yin
D
D
Breau
A P
AP
Paulson
S K
SK
D000284:Administration, Oral; D000577:Amides / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D007275:Injections, Intravenous; D008168:Lung / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D013777:Tetrazoles / Q000378:metabolism / Q000493:pharmacokinetics*
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