PMID: 8937859Nov 1, 1996Paper

Pharmacokinetics and steady-state tissue distribution of L- and D-isomers of nitroarginine in rats

Drug Metabolism and Disposition : the Biological Fate of Chemicals
M A Tabrizi-Fard, H L Fung

Abstract

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 ...Continue Reading

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