Pharmacokinetics,metabolism and excretion of an inhibitor of inducible nitric oxide synthase,L-NIL-TA,in dog |
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| Authors: | J Y Zhang Y F Wang M N Milton M Beconi M Chang D Yin |
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| Institution: | 1. Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Skokie, IL, USAji.y.zhang@gsk.com;3. NeoPharm, Inc., 150 Field Drive, Suite 195, Lake Forest, IL 60045, USA;4. Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Skokie, IL, USA;5. Merck Research Laboratories, Rahway, NJ 07065, USA;6. Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139, USA |
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| 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?μg 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. |
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