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 rol e of NO in various central nervous system processes requires use of an inhi bitor selective for neuronal NOS, and is facilitated by knowledge of the ph armacokinetics of the inhibitor. The present project was undertaken to eluc idate the disposition of the selective neuronal NOS inhibitor 7-nitroindazo le (7-NI). A simple, specific HPLC assay was developed with requisite sensi tivity to quantitate 7-NI in serum after administration of pharmacologicall y relevant doses. Further experiments were performed to assess the effects of administered dose on 7-NI disposition. 7-NI displayed marked nonlinearit y, 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 conc entration-independent and does not contribute to the nonlinearity. Various formulations for iv administration of this water-insoluble compound were ev aluated; the optimal vehicle, from the standpoint of 7-NI solubility, appea red to inhibit the clearance of 7-NI from the systemic circulation. Conside ring the nonlinear disposition of 7-NI, knowledge of the pharmacokinetics o f this inhibitor is requisite to designing administration protocols to achi eve the desired magnitude and duration of NOS inhibition. Copyright (C) 200 0 John Wiley & Sons, Ltd.