Metabolic change as an early step in activation

As indicated in Fig. 3.2, it has sometimes happened that a substance thought to be a drug is really a pro-drug which is converted to the actual agent after administration. Thus Trontosil the first of the antibacterial 

Much earlier, it had been shown that phenylarsonic acids, of which the parent is were inactive until converted in the body to the cor- 

Among drugs introduced in the nineteenth century, chloral hydrate (3.21) is reduced in the body to trichloroethanol (3.22) which is also hypnotic (Butler, 1948) and acetanilide (3.23) and phenacetin 3.24) acts as analgesics after metabolism to p-acetamidophenol (3,6) which has now replaced these pro-drugs (Brodie and Axelrod, 1948, 1949). An old suggestion that codeine exerts some of its analgesic effect after demethyla-tion to morphine has been confirmed (Adler, 1963). 

Whenever it is found that there is no correlation between mean plasma concentration and therapeutic effect, the drug must be suspected to be a pro-drug. From such a clue it was established that the antimalarial proguanil (3.25) acted only after cyclization in the body to the dihydro-triazine (cycloguanil) (3,26) (Crowther and Levi, 1953). The pro-drug is almost inactive against cultures of malarial parasites in vitro whereas 3,26) is highly active. 

By similar means, it was foimd that the gametocidal antimalarials derived from 8-amino-6-methoxyquinoline, such as primaquine (i.27), act only after demethylation and oxidation to the corresponding 5,6-quinone (3.28) (cf. Smith, 1956). 

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Metabolic change as an early step in activation. Pro-drugs. 97... 

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