Comparative pharmacokinetics of N^ω-hydroxy-nor-L-arginine, an arginase inhibitor, after single-dose intravenous, intraperitoneal and intratracheal administration to brown Norway rats

Abstract

1. Rodent studies have documented that N(ω)-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, has therapeutic potential in the treatment of cardiovascular and obstructive airway diseases. However, its bioavailability and pharmacokinetics have not been described so far. 2. Anesthetized brown Norway rats were administered single doses of nor-NOHA (10, 30 or 90 mg/kg) intravenously (i.v.), intraperitonealy (i.p.) or via intratracheal (i.t.) instillation of aerosol. Plasma nor-NOHA was assayed using a validated HPLC method. 3. Upon i.v. administration, the mean concentration showed a biphasic decline and its value dropped below 10% of the maximum after 20 min. The pharmacokinetics were linear with the total and inter-compartmental clearances of 33 and 17 mL/min/kg, central and peripheral volumes of distribution of 0.19 and 0.43 L/kg and terminal half-life of 30 min. 4. The average absolute bioavailability of nor-NOHA after i.p. and i.t. delivery was 98% and 53%, respectively. The absorption from the airways was rate-limiting and its extent decreased with the dose. 5. In conclusion, nor-NOHA is rapidly cleared from the plasma in concordance with the short time window of its in vivo inhibitory activity reported in the literature. I.t. instillation of aerosol for topical effects of nor-NOHA in the airways is characterized with significant systemic availability.

Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

“…Some of these synthetic arginase inhibitors, such as nor-NOHA, BEC and ABH, are currently available commercially. However, the use of such molecules for therapeutic purposes has several limitations: poor bioavailability and potential toxicity (BEC, and ABH) [20], very short half-life (nor-NOHA) [21], and also high cost [22]. Considering that the development of arginase inhibitors is of great therapeutic relevance in various human diseases, investigations have been undertaken in order to develop prodrugs of NOHA [23] or optimized ABH by substituting the Cα-amino acid function [12,24,25,26] and by replacing the boronic acid function [27,28,29,30,31].…”

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

“…injections at doses from 10 to 90 mg/kg (Havlinova et al 2013). Modelling of nor-NOHA kinetics in Wistar rats brought several concordant conclusions.…”

“…We have described a high-performance liquid chromatography method for plasma nor-NOHA (Hroch et al 2012). In a subsequent study with brown Norway rats, the pharmacokinetics of nor-NOHA was investigated after single intravenous, intraperitoneal and intratracheal administration at the doses from 10 to 90 mg/kg which were shown to exert pharmacological effects in rats (Havlinova et al 2013). The primary aim of the present study was to study the kinetics of nor-NOHA and its effect on plasma L-arginine after both single-and multiple-dose administration to Wistar rats.…”

Arginase Inhibition Activity of Stem Bark Extract of Caesalpinia pulcherrima

“…6 While nor-NOHA has short half-life. 7 Ethyl acetate extract of Caesalpinia sappan lignum showed IC 50 value of 36.82 μg/mL to arginase II. Brazilin, the purified compounds of C. sappan, belonged to homoisoflavonoids, have endothelial dependent vasorelaxant activity.…”