Pharmacophoreinduced Toxicity

This involves findings relating to the pharmacology of the compound. Within this category the adverse effects are either a direct or an indirect extension of the pharmacology. With the indirect extension the original selectivity of the compound for a target is lost at elevated doses and the effects seen are triggered by effects on proteins etc., which are closely related structurally to the original target. Pharmacophore-in-duced toxicity is usually seen at doses in excess of the therapeutic dose.

Pharmacophore-induced toxicity does not necessarily occur within the organ or site of intended therapy. An example of this is the toxicity of loop diuretics [1]. The target for this class of drugs are the Na-(K)-Cl co-transporters of the kidney. These co-transporters play a major role in the ion transport and fluid secretion of the utricle and semicircular canal of the ear. Perhaps not surprisingly loop diuretics are associated with ototoxicity. The selectivity and potency of various diuretics can explain their different toxicity profiles. Kidney-specific co-transporters ENCC1 and ENCC2 are expressed in the thick ascending limb and distal convoluted tubule, respectively. ENCC3 is expressed in many tissues including the cochlea. Thiazide diuretics only have activity against ENCC1 and show no toxicity. Loop diuretics inhibit NKCC2 with potencies for bumetanide <0.2 ^M and NKCC3 >0.5 ^M. The selectivity of the compound for NKCC2 is lost under the conditions which cause ototoxicity: intravenous administration of high doses.

Unexpected or polypharmacology in a structure can occasionally lead to additional benefits in drugs. In the same way polypharmacology can have dramatic consequences in toxicity. Thalidomide was used as an anti-nausea drug to control morning sickness. Its use in pregnant women had terrible consequences due to the teratogenic nature of the drug.

Recently thalidomide and some of its metabolites (Figure 8.1) and related analogues have been shown to be inhibitors [2] of hFGF- and VEGF-induced neovascularization (angiogenesis). Such a finding readily provides an hypothesis for the causes of teratogenicity associated with thalidomide, since limb development (the site of teratogenesis) is dependent on the formation of new blood vessels.

A problem with toxicity produced by an extension of the pharmacology of a compound, is that the conventional use of no-effect doses based on pre-clinical animal studies may not apply. Moreover pre-clinical studies may be complicated by the often understated ranges of response seen across species due to species differences in the receptors, enzymes and ion channels that comprise drug targets. Table 8.1 lists some of these known variations and the consequences range from an exaggerated response, to an absence of a response.

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