Metabolic disposition of pyrazinamide in the rat: Identification of a novel in vivo metabolite common to both rat and human

Only limited studies have been reported on the disposition and pharmacokinetics of pyrazinamide (PZA) in both animals and humans. The metabolism of PZA has never been completely elucidated, consequently the metabolites of PZA, pyrazinoic acid (PA), 5‐hydroxypyrazinoic acid (5‐HOPA), and 5‐hydroxypyrazinamide (5‐HOPZA) were characterized and the disposition of PZA was examined following administration of 150mg kg−1 of 14C‐PZA to male Wistar rats. Comparable t1/2 for total radiolabel 14C (1.45 ± 0.06h) and PZA (1.39 ± 0.04h) in the blood compartment were observed. Cumulative 48 h excretion in urine and faeces accounted for 82.6 ± 3.2 per cent and 11.0 ± 1.3 per cent, respectively, of the dose administered. In the 0‐6h urine collections PA, 5‐HOPA, 5‐HOPZA, and PZA, respectively, accounted for 25.4 ± 1.7, 17.7 ± 1.2, 11.6 ± 0.8, and 2.7 ± 0.2 per cent of the administered dose. In the 6–12 h urine samples the proportions of PA and 5‐HOPA increased statistically over the 0‐6h excretion whereas 5‐HOPZA decreased. Administration of PZA to humans indicated 5‐HOPZA was a major urinary metabolite in human. These data suggested that direct hydroxylation of PZA was an alternative pathway in the oxidation of PZA of importance to both human and rat.