In a three-phase study, single oral doses of placebo, followed in 1 week by pyrazinoylguanidine (PZG; 900 mg), followed in 3 weeks by pyrazinoic acid (PZA; 300 mg) were given to 8 normal male ...subjects. Blood analyses performed 0, 2 and 4 h after administration of placebo or drug revealed that compared to mean 0 h values, PZG and also PZA, but not placebo, decreased mean values for serum glucose, insulin, C-peptide, triglycerides and free fatty acids. In all groups, serum potassium, urea, fibrinogen, high-density lipoprotein and low-density lipoprotein were unchanged. PZA, but not PZG, increased serum uric acid. PZG significantly reduced very-low-density lipoprotein whereas PZA only tended to do so. PZG was well tolerated and without any side effect, but in 7 of the 8 normal volunteers, PZA produced a variable vasomotor response over the blush area of the face and neck lasting from 30 min in 3 subjects to 4 h in 1 subject. Collectively, these results suggest generally similar metabolic responses of normal subjects to PZG and PZA after only a single oral dose of each. Previously, it was unrecognized that acute administration of PZG and PZA could produce such rapid metabolic changes.
A reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of pyrazinamide and its metabolites in urine. Study of the metabolism of pyrazinamide ...by this method demonstrated that 5-hydroxypyrazinamide excretion was compatible with pyrazinoic acid excretion and allopurinol decreased in vivo conversion of pyrazinamide to 5-hydroxypyrazinamide and blocked that of pyrazinoic acid to 5-hydroxypyrazinoic acid.
Pyrazinamide, the amide of pyrazinoic acid, is one of the basic therapeutic agents currently used in combination for chemotherapy of tuberculosis. A reversed-phase high-performance liquid ...chromatography method based on ionic pair chromatography, was developed after solid-phase extraction of the analytes from plasma with prior addition of internal standard. The main metabolites, pyrazinoic acid, 5-hydroxypyrazinoic acid and 5-hydroxypyrazinamide, were included as well as uric acid and other purine derivatives to allow detailed study of the pharmacokinetics of the drug, especially in patients with impaired kidney function. Some interesting features of the chromatographic system giving some insight in the retention mechanism and of the solid-phase extraction are discussed in detail.
N-{3-4′-(2″, 6″-Dimethylheptyl)phenylbutanoyl}ethanolamine (E5050), a newly synthesized compound, was shown recently to induce uricosuria in humans via inhibition of the postsecretory reabsorption of ...urate. We examined the effects of this compound on urate excretion in rats loaded with oxonate and compared these effects with those of the uricosuric drugs trichlormethiazide and probenecid. When administered i.p., E5050 (0.3-15 mg/kg) increased the urinary excretion rate of urate and the ratio of urate clearance to inulin clearance in a dose-dependent manner, while the urine volume increased only slightly, and the glomerular filtration rate and plasma urate level were not changed. No paradoxical effect on urate excretion was observed. In contrast, trichlormethiazide and probenecid had a biphasic effect on urate excretion. In a pyrazinoic acid suppression test, the uricosuric effect of E5050 was completely inhibited by pretreatment with pyrazinoic acid. In a Phenolsulfonphthalein (PSP) test, E5050 did not affect urinary PSP excretion, while probenecid strongly decreased such excretion. Thus, E5050 also appears to be uricosuric in rats.
The pharmacokinetics of pyrazinamide (Pirilène) and its metabolites are evaluated in ten subjects with hepatic insufficiency, after an oral dose of 19.3 +/- 0.6 mg.kg-1 and the results are compared ...to those of a group of nine healthy subjects (control group). The results exhibit a marked reduction of the pyrazinamide total clearance (0.48 vs 0.84 ml.min-1.kg-1) and an increase in half-life from 9.19 h to 15.07 h in the patients group. The area under the curve of pyrazinoic acid (the main metabolite) is increased from 97 to 280 mg.h.l-1 with a half-life twice as much as that of the control group. The hepatic insufficiency entails a marked reduction of the common posology as well as a closer survey of the biologic hepatic parameters and of uric acid the renal elimination of which is inhibited by pyrazinoic acid.
PDF
