Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasma and urine pharmacokinetic parameters of pyrazinamide and of its metabolites (pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid and pyrazinuric acid) have been studied after a single oral dose of pyrazinamide 27 mg.kg-1 in 9 healthy subjects. Pyrazinamide was rapidly absorbed (tmax less than or equal to 1 h) and showed a short distribution phase followed by an elimination phase of t1/2 beta = 9.6 h. The close similarity of the apparent elimination rates of the metabolites led to a second trial of a single oral dose of pyrazinoic acid to evaluate the formation and elimination stages. The limiting factor was found to be the activity of a microsomal deamidase (pyrazinoic acid formation from pyrazinamide and 5-hydroxy-pyrazinoic acid formation from 5-hydroxy-pyrazinamide). In contrast, oxidation by xanthine oxidase occurred very rapidly (5-hydroxy-pyrazinamide formation and pyrazinoic acid catabolism to 5-hydroxy-pyrazinoic acid).
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PMID:Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. 273 33

Pyrazinamide (PZA) is increasingly used with isoniazid and rifampicin, in short-course antituberculous chemotherapy in service programme conditions. Complicating arthralgias occur due to hyperuricaemia induced by the inhibition of renal tubular secretion of uric acid by pyrazinoic acid, the main PZA metabolite. Allopurinol (Al), a hypouricaemic agent, provides no substantial clinical improvement. Pharmacokinetics of PZA and its metabolites were studied in six healthy volunteers, in a cross-over design, after a single oral dose of PZA alone and, in a second trial, after the same dose together with Al. Plasma and urinary concentrations were measured by high pressure liquid chromatography with a column of cation exchange resin. Analysis of the pharmacokinetic parameters showed that Al induced marked changes in levels of PZA metabolites and accumulation of pyrazinoic acid. Despite decreasing uric acid synthesis, allopurinol increased plasma concentrations of pyrazinoic acid, which is directly responsible for the inhibition of renal urate secretion. Other drugs, which do not involve xanthine oxidase inhibition, should be used in the treatment of this side effect of chemotherapy.
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PMID:Interaction between allopurinol and pyrazinamide. 322 78

Pyrazinamide (PZA) is widely used in combination with other drugs in chemotherapy for tuberculosis. However, the dose-related liver injury is the main adverse effect of PZA and its metabolite [pyrazinoic acid (PA)]. Silibinin is the main flavonoid extracted from milk thistle (Silybum marianum), and it displays hepatoprotective properties. This study investigates the pharmacokinetics of PZA and PA and their interaction with silibinin in rats. The parallel study design was divided into six groups: PZA alone, PZA + long-term silibinin exposure, PZA + concomitant short-term silibinin exposure, PA alone, PA + long-term silibinin exposure, and PA + concomitant short-term silibinin exposure groups. The results indicate that the distribution ratio of PZA from bile to blood [area under the curve (AUC)(bile)/AUC(blood)] in the PZA + long-term silibinin exposure and PZA + concomitant short-term silibinin exposure groups was also not significantly different when compared with the PZA alone group. However, the bile-to-blood distribution ratio of PA was significantly decreased in the PA + long-term silibinin exposure and the PA + concomitant short-term silibinin exposure groups. On PZA administration, the blood, but not bile, levels of PA were markedly increased in the PZA + long-term silibinin exposure and PZA + concomitant short-term silibinin exposure groups, but the bile-to-blood ratio of PA was decreased. These results suggest that the excretion pathway of PA may be blocked by silibinin through xanthine oxidase and hepatobiliary excretion.
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PMID:Effect of silibinin on the pharmacokinetics of pyrazinamide and pyrazinoic acid in rats. 1754 Jul 7

Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit longstanding paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug.
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PMID:Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives. 2608 40