The poor bioavailability of rifampicin from fixed‐dose combinations containing isoniazid has been attributed to isoniazid‐catalysed degradation under acid conditions in the stomach. The mechanism by which isoniazid enhances rifampicin degradation is not known. The aim of this study was to determine the role of isoniazid in rifampicin decomposition.
Degradation studies were performed in 0.1 M HCl at 37°, in absence and presence of isoniazid. Both rifampicin and isoniazid were analysed. The degradation of rifampicin was increased approximately threefold in the presence of isoniazid. Isoniazid itself was degraded to a lesser extent amounting to one‐fifth of the fall of rifampicin. HPLC studies revealed that decomposition of rifampicin in acidic conditions in the absence of isoniazid stopped at the formation of 3‐formylrifamycin, while the reaction in the presence of isoniazid proceeded to form a hydrazone between 3‐formylrifamycin and isoniazid. The existence of hydrazone was confirmed by its isolation on a preparative column and comparison with an authentic sample synthesized from reaction of 3‐formylrifamycin with isoniazid.
We suggest that once 3‐formylrifamycin is formed, it interacts with isoniazid to form the hydrazone, through a fast second‐order reaction. As hydrazones are unstable in acid conditions, 3‐formylrifamycin and isoniazid are regenerated in a reversible manner through a slower first‐order reaction. In this complex reaction process, rifampicin is further degraded, while isoniazid is recovered.
The extent of decomposition of rifampicin in the presence of isoniazid was determined in the pH range 1-3 at 37 degrees C in 50 min, the mean stomach residence time. With increase in pH, the degradation initially increased from pH 1 to 2 and then decreased, resulting in a bell-shaped pH-decomposition profile. This showed that rifampicin degraded in the presence of isoniazid to a higher extent at pH 2, the maximum pH in the fasting condition, under which antituberculosis fixed-dose combination (FDC) products are administered. At this pH and in 50 min, rifampicin decomposed by approximately 34%, while the fall of isoniazid was 10%. The extent of decomposition for the two drugs was also determined in marketed formulations, and the values ranged between 13-35% and 4-11%, respectively. The extents of decomposition at stomach residence times of 15 min and 3 h were 11.94% and 62.57%, respectively, for rifampicin and 4.78% and 11.12%, respectively, for isoniazid. The results show that quite an extensive loss of rifampicin and isoniazid can occur as a result of interaction between them in fasting pH conditions. This emphasizes that antituberculosis FDC formulations, which contain both drugs, should be designed in a manner that the interaction of the two drugs is prevented when the formulations are administered on an empty stomach.
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