Suggesting a testing strategy for possible endocrine effects of drug metabolites

Most pharmaceuticals are extensively metabolized by organisms, which results in internal exposure to mixtures of parent compounds and various metabolites. Many of these metabolites are considered non-toxic, but some metabolites retain toxic properties of the parent compound or elicit other undesirable outcomes. Unfortunately, the effects of metabolites are often not considered when endocrine activities of chemicals are evaluated in vitro. In this study two approaches, an “effect-based” and a “compound-by-compound” testing design, were used to determine the effects of metabolites of the antidepressant sertraline on aromatase enzyme activity. In the “effect-based” approach, a mixture of sertraline metabolites, produced by liver microsomes, inhibited aromatase, but was less potent than sertraline. In the “compound-by-compound” testing design, three specific metabolites were evaluated individually and in mixtures. Though two N-desmethylated metabolites were more potent aromatase inhibitors than sertraline, hydroxyl ketone sertraline did not inhibit the enzyme and mixtures of these metabolites and sertraline were less potent than predicted from a concentration addition model. Our findings highlight the importance of considering aromatase inhibition, and potentially other biological activities, of pharmaceutical metabolites produced by liver microsome preparations and then comparing such observations to studies of specific metabolites available for testing in pure form. Subsequently, a five step integrated strategy for screening of the potential endocrine effects of drugs and their metabolites are proposed.

► Adverse endocrine effects of sertraline metabolites are studied. ► Two testing approaches are compared: compound by compound (CC) and effect based (EB). ► CC show that some metabolites are more potent than sertraline. ► EB show a mixture of metabolites formed in vitro to be less potent than sertraline. ► A testing strategy combining EB with CC is suggested for evaluation of metabolites.