Metabolites with Dissimilar Actions

In certain instances, the body converts a drug to several active metabolites possessing dissimilar pharmacologic properties. For example, phenylbutazone undergoes aromatic hydroxylation to produce a metabolite that has sodium-retaining and antirheumatic activities, and also undergoes alkyl chain oxidation to produce a metabolite with a strong uricosuric property. Thus, phenylbutazone has both uricosuric and antirheumatic effects. 

---

The assumption of concentration addition is not a priori justified because only compounds with the same mode of toxic action will act concentration additive in mixtures [15]. If parent compoimd and metabolites act according to different modes of toxic action, the appropriate mixture toxicity model would be independent action [16]. A mixture of similarly and dissimilarly acting compounds would have to be assessed with a two-step model [17]. This approach is too complicated for our screening purposes. Moreover, the necessary information to distinguish between different modes of toxic action (moa) is missing in most cases. However, if there are only a small number of chemicals in a mixture, the predictions for concentration addition are often very similar to the observed effects in mixtures of compounds with different moa [ 18,19]. Therefore, in our case of a mixture of one parent compound and a small number of metabolites, the use of concentration addition as so-called realistic worst-case scenario is justified. 

---