The antitumor drug pyrazine-2-diazohydroxide exhibits cytotoxicity to A204 tumor cells in vitro under acid conditions. The IC50 with a 1 hr drug exposure at pH of 7.4 was 61 micrograms/ml and at pH of 6.0 it was 31 micrograms/ml. It is suggested that the increased cytotoxicity is due to the acid catalyzed formation of a reactive pyrizinyldiazonium ion from pyrazine-2-diazohydroxide. Pyrazine-2-diazohydroxide is also more cytotoxic to A204 cells under hypoxic conditions in the presence of glucose with an IC50 at pH 7.4 of 22 micrograms/ml. The increased cytotoxicity of pyrazine-2-diazohydroxide under acid and hypoxic conditions may favor selective toxicity to solid tumors in vivo. Coincubation with rat hepatic microsomes increased the cytotoxicity of pyrazine-2-diazohydroxide to A204 cells. The effect did not require NADPH and was not due to formation of metabolites. There was an increased rate of degradation of pyrazine-2-diazohydroxide in the presence of microsomes, presumably with formation of the pyrizinyldiazonium ion. The final degradation product 2-hydroxypyrazine was not cytotoxic to A204 cells. The effect of microsomes on pyrazine-2-diazohydroxide cytotoxicity is probably of little in vivo significance.
The pharmacokinetics and metabolism of pyrazine-2-diazohydroxide have been studied in the beagle dog and mouse. When pyrazine-2-diazohydroxide was administered to beagle dogs at a dose of 18.6 mg/kg (428 mg/m2) by i.v. bolus, the plasma half-life (t1/2) was 7.3 min, the apparent volume of distribution (Vd) 577 ml/kg, and the total body clearance (Cl) 55 ml/min per kg. In mice given pyrazine-2-diazohydroxide by i.v. bolus at 100 mg/kg (428 mg/m2), the t1/2 was 5.8 min, the Vd 250 ml/kg, and the Cl 30 ml/min per kg. When [2-14C]pyrazine-2-diazohydroxide was infused i.v. to mice at 100 mg/kg over 8 h, the Cl for parent drug was 122 ml/min per kg. The major product formed from pyrazine-2-diazohydroxide was 2-hydroxypyrazine, which accounted for 80% of the total radioactivity in the plasma after a 6-h drug infusion. There were three other metabolites in plasma, two more polar than pyrazine-2-diazohydroxide, which accounted for 7% of the radioactivity, and one less polar, which accounted for 5% of the radioactivity. Following an i.v. bolus dose of [2-14C]pyrazine-2-diazohydroxide, 79% of the radioactivity was excreted in the urine in 24 h, 3% in the feces, and 0.4% in the expired air; 18% remained in the carcass. The liver and kidney showed the highest tissue levels of radioactivity. 2-Hydroxypyrazine accounted for 45% of the urinary radioactivity, pyrazine-2-diazohydroxide for 14%, and a glucuronide or sulfate conjugate of 2-hydroxypyrazine for 17%. Twenty-four percent of the radioactivity eluted near the void volume on high-performance liquid chromatography and was not identified.
The chemical breakdown of carmethizole [1-methyl-2-methylthio-4,5-bis-(hydroxymethyl)imidazole-4',5'- bis(N-methylcarbamate)hydrochloride] and its pharmacokinetics in the mouse and beagle dog were studied. Carmethizole was relatively unstable in aqueous media, having a half-life of less than or equal to 1 h in 0.9% sodium chloride, human whole blood, human plasma, and dog urine at 37 degrees C. Its major breakdown product in 0.9% sodium chloride and pH 5.0 sodium phosphate buffer was carmethizole diol. When carmethizole was added to pH 7.0 or pH 9.0 sodium phosphate buffer, the major breakdown product was carmethizole diol-4'-monophosphate. Carmethizole reacted directly with glutathione at pH 8.0, forming a glutathione adduct of carmethizole monocarbamate. Elimination of the drug from the plasma of the beagle dog following i.v. bolus doses of 22.4 and 4.3 mg/kg was biphasic. At these doses the terminal half-life was 39 and 46 min, respectively, and the respective total body clearance was 4.6 and 7.7 ml/min per kg. The 22.4 mg/kg dose was lethal to the beagle dog by day 4. Elimination of carmethizole from the plasma of mice following an i.v. bolus dose of 115 mg/kg was monoexponential, with a half-life of 11.6 min and a total body plasma clearance of 43.6 ml/min per kg. When the drug was infused at 230 mg/kg over 8 h into mice, the total body clearance was 40.8 ml/min per kg. Following the i.v. bolus administration of carmethizole to mice, 30% of the total dose was excreted in urine over 3 h as carmethizole diol, 10%, as carmethizole diol-sulfate, 3.4%, as carmethizole 4'-monocarbamate, and 2.4%, as unchanged drug.
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