Relationship between steady-state pharmacokinetics and hemodynamic effects of inhaled isobutyl nitrite in conscious rats

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Relationship between steady-state pharmacokinetics and hemodynamic effects of inhaled isobutyl nitrite in conscious rats

Journal Title: The AAPS Journal - Year 2000, Vol 2, Issue 2

Abstract

Our objective was to examine the pharmacokinetic/hemodynamic properties of inhaled isobutyl nitrite (ISBN) in rats. ISBN is one of the volatile organic nitrites that has been used primarily as a drug of abuse. Recent studies indicate, however, that these compounds may be superior to organic nitrates for cardiovascular use because they do not produce vascular tolerance. Rats inhaled ISBN over an exposure range of 20 to 1200 ppm for 1 hour. The effects of ISBN on blood pressure and heart rate were determined and blood concentrations of ISBN were analyzed with use of gas chromatography. Apparent steady-state blood levels of ISBN were achieved during inhalation and were linear with exposure concentration (blood concentration: 0.05 to 3.5 μM: exposure concentration: 23 to 1177 ppm; r2=0.92). Inhaled ISBN caused rapid, dose-dependent, and parallel reductions in systolic and diastolie pressure, while heart rate increased maximally to 22%. A sigmoid Emax model could describe the mean arterial pressure effect of inhaled ISBN (Emax=55%; EC50=0.51 μM). After inhalation, blood pressure and heart rate quickly returned to baseline, without any withdrawal rebound effect. Inhaled ISBN produced a rapid onset of action on heart rate and blood pressure, and these effects were sustained over 60 minutes of exposure. Abrupt drug withdrawal did not lead to hemodynamic rebound. The blood pressure effects were related to ISBN blood concentration by the sigmoid Emax model. These results provide new information on the pharmacokinetic pharmacodynamic relationship of a representative nitrite inhalant.

Authors and Affiliations

William Kielbasa, Ho-Leung Fung

Keywords

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The online version of this article (doi:10.1208/s12248-012-9407-9) contains supplementary material, which is available to authorized users.

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EP ID EP682079
DOI 10.1208/ps020211
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