Single- and multiple-dose pharmacokinetics of arginase inhibitor N-omega-hydroxy-nor-L-arginine, and its effect on plasma amino acids concentrations in Wistar rats
Abstract
Arginase inhibitor N-ω-hydroxy-nor-L-arginine (nor-NOHA) augments synthesis of nitric oxide (NO) exerting therapeutic effects in rodent models for cardiovascular and airway diseases. This study examined single- and multiple-dose pharmacokinetics and effects of nor NOHA on plasma amino acids in Wistar rats.
Animals were administered 30 mg/kg nor NOHA in a single bolus intravenous (i.v.) or intraperitoneal (i.p.) injection, or five once-daily i.p. injections at the same dose, or vehicle. Nor-NOHA and amino acids were assayed in blood plasma by high-performance liquid chromatography.
After a bolus i.v. injection, the elimination of nor-NOHA was rapid (the mean residence time=12.5 min). The area under the concentration-time curve and maximum concentration were higher by 17% and 31%, respectively, after the fifth as compared to the first i.p. injection.
A shift in arginine utilization towards the synthesis of NO was indicated by elevated citrulline-to-ornithine and citrulline-to-arginine ratios. No changes in plasma arginine were observed.
Increased glutamine concentrations might indicate an alternative detoxification pathway for ammonia due to inhibition of hepatic arginase. In conclusion, pharmacokinetic data of the present study can guide rational dosing of nor-NOHA in future studies.
Limitations of the stratégy of NO modulation via arginase inhibition should be further explored.