Pharmacokinetics and steady-state tissue distribution of L- and D-isomers of nitroarginine in rats.
Nitric oxide synthase (NOS) inhibitors, such as nitro-L-arginine (L-NNA), have been used in vivo as mechanistic probes of the NOS system and as potential therapeutic agents for reversing the hypotension developed in septic shock. Little information is available regarding the pharmacokinetic and biodistribution pattern of these compounds. We have examined the in vivo disposition, as well as steady-state biodistribution, of NNA isomers in rats. Plasma and tissue concentrations of L-NNA were determined by HPLC. After intravenous administration of a bolus dose of 20 mg/kg in rats, plasma concentrations of both L- and D-NNA declined biexponentially, with average half-lives of 12 min and 20 hr for L-NNA, and 15 min and 15 hr for the D-enantiomer, respectively. In contrast to L-NNA, the D-isomer had a higher systemic clearance (170 +/- 20 vs. 70.9 +/- 8.2 ml/hr/kg; p = 0.0004) and shorter mean residence time (17.3 +/- 3.7 vs. 31.7 +/- 3.7 hr; p = 0.0039). Based on these pharmacokinetic characteristics, steady-state plasma concentrations of NNA isomers were achieved within 6-8 hr through the use of a loading dose and maintenance infusion. NNA concentrations achieved in many tissues exceeded plasma concentrations, indicating binding of the drug to tissue components. The tissue-to-plasma distribution coefficient (Kp) for L-NNA was variable among various tissues and ranged from 0.67 for testes to 3.17 for liver. Both kidneys and skeletal muscle had Kp values higher than 2, whereas distribution to the cerebrospinal fluid was minimal (Kp = 0.09). Steady-state distribution of the D-isomer of NNA was similar to that of L-NNA.
Tabrizi-Fard
M A
MA
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260-1200, USA.
Fung
H L
HL
D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007536:Isomerism; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase