Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole.
Utilization of nitric oxide (NO) synthase (NOS) inhibitors to probe the role of NO in various central nervous system processes requires use of an inhibitor selective for neuronal NOS, and is facilitated by knowledge of the pharmacokinetics of the inhibitor. The present project was undertaken to elucidate the disposition of the selective neuronal NOS inhibitor 7-nitroindazole (7-NI). A simple, specific HPLC assay was developed with requisite sensitivity to quantitate 7-NI in serum after administration of pharmacologically relevant doses. Further experiments were performed to assess the effects of administered dose on 7-NI disposition. 7-NI displayed marked nonlinearity, consistent with saturable elimination, when administered by ip injection in peanut oil. The nonlinearity was related to total dose, but not to the concentration of 7-NI in the vehicle. Binding of 7-NI in rat serum was concentration-independent and does not contribute to the nonlinearity. Various formulations for iv administration of this water-insoluble compound were evaluated; the optimal vehicle, from the standpoint of 7-NI solubility, appeared to inhibit the clearance of 7-NI from the systemic circulation. Considering the nonlinear disposition of 7-NI, knowledge of the pharmacokinetics of this inhibitor is requisite to designing administration protocols to achieve the desired magnitude and duration of NOS inhibition.
Bush
M A
MA
Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Pollack
G M
GM
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005079:Excipients; D006207:Half-Life; D007191:Indazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
D004791:Enzyme Inhibitors; D005079:Excipients; D007191:Indazoles; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole