The Effect of acetaminophen on isoniazid metabolism

Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol), an analgesic and antipyretic drug, causes liver necrosis in overdose. Isoniazid (INH, isonicotinyl hydrazide), an antituberculous drug, also causes liver damage in some patients at therapeutic doses. The two medications are likely to be taken concurrently. Previously we reported that, depending on the condition, INH inhibits or induces the toxic pathway of APAP metabolism. In this study the influence of APAP on INH metabolism was investigated in ten healthy volunteers. INH, 300 mg, was ingested daily for 7 days. APAP, 500 mg, was ingested on the day before starting INH (day 0) and on day 7 of INH ingestion. INH and its major metabolites in urine (days 6 and 7) were analyzed by reversed-phase high-performance liquid chromatography. Two metabolites, isonicotinic acid (INA) and isonicotinylglycine (ING), were analyzed directly by using an isocratic mobile phase system; propionylisoniazid was used as an internal standard. INH and its hydrazine metabolites, hydrazine (Hz) and acetylhydrazine (AcHz), were derivatized with m-anisaldehyde and subsequently analyzed by using a gradient mobile phase system; 9-fluorenone was a standard. A different procedure was used to analyze acetylisoniazid (AcINH) and diacetylhydrazine (DiAcHz). The INH, AcHz, and Hz present in the samples were converted to hydrazones by reaction with p-chlorobenzaldehyde. The hydrazones were then extracted with methylene chloride. The AcINH and DiAcHz remaining in the aqueous layer were then converted to INH and AcHz, respectively, by partial acid hydrolysis. The partial hydrolysis products were derivatized with m-anisaldehyde and then analyzed as above. The 2-tailed paired-sample t test suggested that concomitant APAP ingestion had no effect on the metabolism of INH, but this conclusion is far from certain. A number of explanations are given.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat