Findings related to the structure of the compound but not related to the pharmacology can provide another possible source of toxicity. This category is distinguished by the adverse events or effects being triggered by structural features or physicochemi-cal properties etc. which allow the compound or metabolites to interact at sites distinct from the intended target or related proteins, etc. This type of toxicity can occur at any dose level including the therapeutic dose.
Amiodarone (Figure 8.2) is an efficacious drug that causes a number of side-effects. The presence of iodine in the molecule is unusual and hypo- and hyperthyroidism have been reported in patients. Although the loss of iodine is relatively slow the relatively large daily dose size and long half-life of the drug and its de-ethylated metabolite suggest that the presence of iodine in the molecule is responsible for its toxicity .
The drug is also a highly lipophilic base and accumulates in a number of tissues including the lung. This combination of extreme physicochemical properties can result in more specific interactions such as the condition of phospholipidosis (increase in total lung phospholipids) caused by inhibition of phospholipid breakdown . The medicinal chemist has to decide if extreme lipophilicity and the presence of iodine are essential for activity and, in the case of amiodarone, proven clinical efficacy or whether alternative structures are possible.
Proxicromil and FPL 52757  were oral anti-allergy agents that utilized the strongly acidic "chromone" skeleton as a starting point (Figure 8.3). This skeleton contained the pharmacophore. To achieve oral absorption substantial lipophilicity was added and these changes resulted in surface active (detergent) molecules. The hepatobiliary route of excretion and resultant high concentrations of the compounds at the biliary cannaliculus resulted in hepatotoxicity .
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