Pharmacokinetics of a Model Organic Nitrite Inhalant and its Alcohol Metabolite in Rats

• Published in: Drug metabolism and disposition Vol. 28; no. 4; pp. 386 - 391
• Main Authors: Kielbasa, William, Fung, Ho-Leung
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2000; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Administration, Inhalation; Alcohols - blood; Alcohols - metabolism; Animals; Biological and medical sciences; Biotransformation; Cardiac Output - drug effects; Drug addictions; Half-Life; Infusions, Intravenous; Male; Medical sciences; Nitrites - administration & dosage; Nitrites - blood; Nitrites - pharmacokinetics; Rats; Rats, Sprague-Dawley; Toxicology; Vasodilator Agents - administration & dosage; Vasodilator Agents - blood; Vasodilator Agents - pharmacokinetics; NO; ISBA; ISBN; ISAN; Volatile compound; Intravenous administration; Rat; Metabolite; Nitrites; Rodentia; Metabolism; Inhalation; Toxicokinetics; Vertebrata; Mammalia; Animal; Distribution; Organic nitrate; Models; Drug of abuse
• DOI: 10.1016/S0090-9556(24)15054-4
• ISSN: 0090-9556

Volatile organic nitrites were originally used to relieve the chest pain that is associated with angina pectoris. Today, these inhalants are predominantly used as drugs of abuse. Little is known regarding the bioavailability and disposition of volatile nitrites. In this study, the pharmacokinetics of a major organic nitrite inhalant, isobutyl nitrite (ISBN), and its primary metabolite, isobutyl alcohol (ISBA), were investigated after inhalation and 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/min/kg that vastly exceeded cardiac output (0.3 l/min/kg). Approximately 98% of ISBN was metabolized to ISBA, which declined monoexponentially with a half-life of 5.3 min when the infusion of ISBN was terminated. The bioavailability 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-fold (t1/2 inh = 1.5 min versus t1/2 i.v. = 5.3 min; P < .001), whereas no pharmacokinetic difference was observed for ISBN. Inhalation of another nitrite, isoamyl nitrite, accelerated the apparent clearance of ISBA, suggesting that nitrite inhalation could change the disposition of another compound. A pharmacokinetic model was developed to describe the concentration-time profile of ISBA and ISBN after inhalation and i.v. administration.