Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats

Volatile organic nitrites were originally used to relieve the chest pain th at is associated with angina pectoris. Today, these inhalants are predomina ntly used as drugs of abuse. Little is known regarding the bioavailability and disposition of volatile nitrites. In this study, the pharmacokinetics o f a major organic nitrite inhalant, isobutyl nitrite (ISBN), and its primar y metabolite, isobutyl alcohol (ISBA), were investigated after inhalation a nd i.v. administration. ISBN blood concentrations in the rat declined mono- exponentially with a half-life of 1.4 min and a blood clearance of 2.9 l/mi n/kg that vastly exceeded cardiac output (0.3 l/min/kg). Approximately 98% of ISBN was metabolized to ISBA, which declined monoexponentially with a ha lf-life of 5.3 min when the infusion of ISBN was terminated. The bioavailab ility of inhaled ISBN, over a range of 300 to 900 ppm, was estimated to be 43%. After inhaled ISBN, the half-life of ISBA decreased approximately 4-fo ld (t(1/2) inh = 1.5 min versus t(1/2) i.v. = 5.3 min; P < .001), whereas n o pharmacokinetic difference was observed for ISBN. Inhalation of another n itrite, isoamyl nitrite, accelerated the apparent clearance of ISBA, sugges ting that nitrite inhalation could change the disposition of another compou nd. A pharmacokinetic model was developed to describe the concentration-tim e profile of ISBA and ISBN after inhalation and i.v. administration.