title: Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog.
abstract: 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Skokie, IL, USA. ji.y.zhang@gsk.com
authors.forename: J Y
authors.initials: JY
authors.lastname: Zhang
authors.forename: Y F
authors.initials: YF
authors.lastname: Wang
authors.forename: M N
authors.initials: MN
authors.lastname: Milton
authors.forename: M
authors.initials: M
authors.lastname: Beconi
authors.forename: M
authors.initials: M
authors.lastname: Chang
authors.forename: D
authors.initials: D
authors.lastname: Yin
authors.forename: A P
authors.initials: AP
authors.lastname: Breau
authors.forename: S K
authors.initials: SK
authors.lastname: Paulson
mesh_terms: 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*
chemical_list: 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