It is generally agreed that the metabolic pathway of a drug and its thera peutic activity are relatcd1 2. Some years ag03 metabolic studi e s on the two tuberculostatics 4-pyridyl-oxadiazolone5 and isoniazid, showed that both substances gave in the rat three identical metabolites. This fact was considered sufficient evidence to draw the conc1usion that 4-pyridyl oxadiazolone was metabolised in the body via isoniazid, which latter would be responsible for the tuberculostasis. The two drugs would be therefore clinically identical. Cross resistance studies using the two sub stances against various strains of Mycobacterium tuberculosis showed between 80-90 per cent cross resistance, confirming this view. Studies on 4-pyridyl oxadiazolone5 were therefore stopped, it being considered that it was simply another somewhat less active form of isoniazid. It is proposed here to describe one or two surprises we have experienced in research in the above field in the past few years.
I.If one subcultures H37 Rv in the presence ofjust sub-liminal doses of isoniazid, resistance develops rapidly as shown in Table I. After six sub cultures the minimal inhibitory dose of isoniazid has risen from I : 40 million to I : 80 thousand.But if 4-pyridyl-oxadiazolone is cultured under the same conditions against H37 Rv resistance emergence is much slower (Table I).
2.It seemed, therefore, that the two substances INH and 4-pyridyl oxadiazolone were not absolutely biologically identical, at least in vitro, otherwise the resistance emergence rates would have been identical too.If their biological spectra are not absolutely identical, it was thought likely that, in the presence of 4-pyridyl-oxadiazolone, the resistance emergence rate towards INH would be modified. If the two substances possess exactly the same biological spectrum, a I : I mixture of INH and 4-pyridyl-oxadiazolone should show a resistance emergence rate'