title: 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: Arginase inhibitor Nω-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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic. havlinovaz@lfhk.cuni.cz.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Havlínová
authors.forename: Miloš
authors.initials: M
authors.lastname: Hroch
authors.forename: Andrea
authors.initials: A
authors.lastname: Nagy
authors.forename: Luděk
authors.initials: L
authors.lastname: Sišpera
authors.forename: Milan
authors.initials: M
authors.lastname: Holeček
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chládek
mesh_terms: D000596:Amino Acids / Q000097:blood*; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; D001120:Arginine; D001119:Arginase