Studies on the stability of drugs in biological media. 2. Relationship between the stability in culture media and anti-bacterial activity of some isoniazid derivatives.

Abstract

The relationships between stability in culture media and in vitro anti-bacterial activity against Bacillus Calmette-Guerin (BCG) were investigated with furyl methyl ketone isonicotinoylhydrazone (FKI), glucose isonicotinoylhydrazone (G-INAH), and sodium pyruvate isonicotinoylhydrazone (P-INAH). FKI was found to be essentially equal to isoniazid in its activity under the equimolar basis. Thus its stability which was dominantly affected by several amino acids resulted to have no influence on the evaluation of the activity. On the other hand, a significant relationship was found among G-INAH and P-INAH, which can not inhibit growth of BCG until they release sufficiently large amount of isoniazid by hydrolysis. P-INAH was found to be hydrolyzed with such an extraordinary rapidity as 6 and 23 times greater than G-INAH in Kirchner and Long medium, respectively. This instability inversely related to the enhancement of its activity which consequently resulted in the same one as isoniazid. While G-INAH was observed to be hydrolyzed in Kirchner medium about 4 times as rapidly as in Long medium and it showed to have greater activity in the former than in the latter. The release rate of isoniazid might be inversely proportional to the stability and directly to the activity of these drugs. Another in vitro experiment with drug exposure times suggested that the bactericidal effect of drugs was probably displayed in the relatively early stage of test incubation period.