Pyrazinamide. oxidation

In many other cases, hydrolysis results in drug inactivation, as with the tuberculostatic agent pyrazinamide (4.69). In humans and rats, the metabolism of this compound involves deamidation to produce pyrazinoic acid (4.70). Ring oxidation is another major pathway, leading to 5-hydroxypyrazinamide (4.71), which, in turn, is hydrolyzed to 5-hydroxypyrazinoic acid (4.72). The rates of hydrolysis were found to determine the apparent half-life of pyrazinamide [42] [43]. 

Pyrazinamide can only be administered orally. It has a protein binding of 10-20% and is widely distributed, also to the CNS. Pyrazinamide undergoes deamination and oxidation in the liver with urinary excretion of the metabolites. Its elimination half-life is approximately 10 h. Combination with other drugs is mandatory as resistance occurs rapidly. 

This process was undoubtedly developed for the manufacture of pyrazinamide (Zinamide, etc.),1696 a second-line drug for Mycobacterium tuberculosis infections, resistant to more effective and less toxic agents. Thus a mixture of 2-methyl-pyrazine (323), ammonia, oxygen, and steam is passed (at 400°C) over an alumina- or pumice-supported catalyst comprising one to three oxides of Ce, Cr, Mo, Mn, P, Sb, Ti, or (most importantly) V the main product (in up to 90% yield) is 2-pyrazinecarbonitrile (324), easily converted into 2-pyrazinecarboxamide... 

Nicotinamide (34) and structurally related 51 compounds were subjected to the halting activity bioassay to elucidate the structure-activity relationships [105]. The highest activity was recorded in thionicotinamide (35) followed by pyrazinamide (36) and nicotinamide (34). Nicotinamide adenine dinucleotide (NAD) (oxidized form), nicotinamide adenine dinucleotide phosphate (NADP) (oxidized form), (3-nicotinamide mononucleotide (oxidized form) showed halting activity at ca. 10"7 M... 

Pyrazinamide is readily absorbed after oral administration, but little of the intact molecule is excreted unchanged (Fig. 41.9). The major metabolic route consists of hydrolysis by hepatic microsomal pyrazinamidase to pyrazinoic acid, which may then be oxidized by xanthine oxidase to 5-hydroxypyrazinoic acid. The latter compound may appear in the urine either free or as a conjugate with glycine (23). 

It is effective in lowering blood sugar and FFA levels in intact, adrenalectomized and hypophysectomized rats. This compound is metabolized to 2-carboxy-pyrazine, which is responsible for its action. 39 This is substantiated by the finding that pyrazinamide does not increase glucose oxidation or inhibit FFA release from adipose tissue in vitro whereas 2-carboxypyrazine exerts both actions. Hypoglycemic activity is attributed to the ability of 2-carboxypyrazine to increase glucose utilization in adipose tissue. 39... 

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