Single- and multiple-dose pharmacokinetics of arginase inhibitor Nω-hydroxy-nor-L-arginine, and its effect on plasma amino acids concentrations in Wistar rats

Abstract

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 was 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 strategy of NO modulation via arginase inhibition should be further explored.

Neutrophil degranulation and myocardial infarction

“…Moreover, Nor-NOHA showed significantly decreased infarct size after intracoronary treatment [ 135 ]; however, nor-NOHA presented no significant effect for reducing infarct size after intravenous treatment [ 135 ]. This might be explained by the rapid elimination (the mean residence time was 12.5 min) and high clearance owing to hydroxyguanidine chemical and metabolic lability [ 138 ]. Researches have been investigating new arginase inhibitors with characteristics of low clearance, long t1/2, and moderate volume distribution [ 139 ].…”

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

“…The inhibitory activity difference between NOHA and nor-NOHA highlighted the importance of the chain length between the α-amino acid and the hydroxyguanidine function for the recognition by arginase and for further specific interaction with the binuclear Mn 2+ cluster of the active-site, conferring selectivity to arginase over NOS [ 119 , 124 ]. Pharmacokinetics of nor-NOHA was evaluated in rat models, showing short in vivo target residence time (τ = 12.5 min [ 125 ]) and rapid clearance from the plasma (elimination half-life approx. 30 min [ 126 ]).…”

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases

“…In particular, no apparent toxicity was present following 20 min [ 125 ] of intra-arterial infusion of nor-NOHA at a dose of 0.1 mg/min in CAD patients. And the oral bioavailability (F) of NOHA and nor-NOHA is sufficient, with F values of more than 50% [ 149 ]. Because of the hydroxyguanidine chemical and metabolic lability [ 149 ], nor-NOHA presents rapid elimination with t 1/2 of 30 min and can be rapidly cleared from the plasma in concordance [ 150 ].…”