Substances whose biological action is at least partly due to chelation

9 Substances whose biological action is at least partly due to chelation 

Many other chelating agents have found widespread employment in medicine. Although, because of their constitution, they could not fail to combine with heavy metals in the tissues, enough is not always known of their mode of action to decide whether they act by chelation alone. Yet, no matter how much or little their chelating properties may govern the mode of action, these properties deserve study because of their role in absorption and the causation of side effects. 

In the presence of cupric ions, isoniazid is taken up much more rapidly by M. tuberculosis H27 Rv., in culture (Youatt, 1962). Blood serum copper (see p. 433) is maintained at a low level, but, bearing in mind the small number of bacteria that sustain an infection and the length of the treatment, quite sufficient copper is available to convert a therapeutic concentration of the drug into its chelate. However, the action of isoniazid cannot be due entirely to chelation, because neither of its two isomers has any notable action against M. tuberculosis, even in vitro, although their stability constants are as high, or even higher (Albert, 1956). This is shown in Table 11.12. It is known that isoniazid enters the cells of non-resistant tubercle bacteria, and does not penetrate the cells of resistant strains also the common bacterial species such as Staph, aureus and E. coli, which are never affected by isoniazid, do not absorb it (Youatt, 1958). 

It seems fairly certain that chelation with trace copper makes the drug liposoluble enough to penetrate the most lipophilic of all bacterial integuments, but the question remains what happens next The answer was first outlined by Kriiger-Thiemer (1957), and has since become firmly supported (Seydel et al.. 

It was once thought that isoniazid acted on Mycobacteria by combining with pyridoxal. This was soon disproved, but some side effects on the patient have been traced to this reaction. 

Isoniazid (11,31). This substance, the hydrazide of isonicotinic acid, is the keystone of the modern treatment of tuberculosis. It has an affinity for the ions of heavy metals of the same order as that of glycine. The complexes (11.33) of isoniazid are formed through the anion (11,32). No anion can be formed by the methyl-derivative N-methyl-N-isonicotinoylhydra-zine (11.34), tid this substance has virtually no antitubercular activity (Cymerman-Craig and Willis, 1955 Cymerman-Craig et al., 1955). Thus isoniazid inhibited Mycobacterium tuberculosis Rv. (in vitro, in the presence of 10 per cent of serum) at M/5000000, but substance (11.34) was inactive. 

Seydel and his colleagues (1976b) synthesized the isonicotinic analogue and found it identical with material isolated from the strain of M, tuber- 

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