Antiparasitics, human

Avermectins and Ivermectin. The avermectias are pentacycHc lactones isolated from fermentation products of Streptomjces avermitilis and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectia (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fmits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde gmbs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). 

By contrast, when allopurinol riboside (11.19), a metabolite of allopuri-nol and an antiparasitic agent, is administered orally to humans, the drug is incompletely absorbed. The residual fraction is then extensively metabolized by the enteric flora to produce metabolites that are absorbed [41], Bacterial metabolism proceeds by cleavage to allopurinol, a reaction that apparently occurs only in the intestine. Although the examples described pertain to different animal species, it is clear that small structural changes can elicit major differences in metabolism. 

Since mitochondria are energy factories, they are essential to cellular life. This fact can be usefully exploited in drug design to enable selective killing of unwanted cell types. For example, the mitochondria of certain parasites are fundamentally different from those of the host human cells. Accordingly, it is possible to selectively kill such parasites by targeting the biochemical uniqueness of their mitochondria. Certain 4-hydroxyquinoline derivatives are effective antiparasitic agents that use this mechanism. 

Campbell WC (1991) Ivermectin as an antiparasitic agent for use in humans. Annu Rev Microbiol 45, 445-474. 

The use of pyridine and quinoline derivatives in the growth of poultry and related animal industries is described in CHEC(1984) <1984CHEC(2)511>. In CHEC-II(1996) <1996CHEC-II(5)245>, discussion of veterinary products had subsections covering anthelmintics, antiparasitics, and antibacterials. It is pointed out in CHEC-II(1996) <1996CHEC-II(5)245> that drugs developed for human use often find a place in veterinary medicine. 

Figure 27 Metabolism of DB289 (antiparasitic prodrug) by a panel of recombinant human CYP enzymes. Abbreviation CYP, cytochrome P450.

Wang MZ, Saulter JY, Usuki E, et al. CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-0-methylamidoxime]. Drug Metab Dispos 2006 34 1985-1994. 

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