The reason for an increase in decomposition of rifampicin in the presence of isoniazid under acid conditions

Abstract

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.