Qualitative Analysis of the Role of Metabolites in Inhibitory Drug-Drug Interactions
In a recent guidance, the Food and Drug Administration recommended safety studies of metabolites. This guidance applied primarily to the metabolites formed specifically in humans for which toxicity could not be predicted by animal testing. However, in addition to directly mediating toxicity metabolites may also be responsible for Cyp inhibition. Preclinical animal studies are not predictive of potential drug-drug interaction which can become problematic. In two recent articles, Dr. Nina Isoherranen et al. presented results of literature analysis using the Metabolism and Transport Drug Interaction Database. Specifically, they found that in DDI studies where ther is a 20% increase in the area under the plasma concentration-time curve (AUC) of marker substrates, that 106 out of 129 inhibitors were confirmed to have metabolites that circulate in plasma. These data support that circulating metabolites are often present with inhibitors of P450 enzymes, suggesting a need for increased efforts to characterize the inhibitory potency of metabolites of candidate drugs and for newer models for in vitro to in vivo extrapolations.
1. Nina Isoherranen, Houda Hachad, Catherine K. Yeung, and Rene H. Levy. Chem. Res. Toxicol. 2009, 22, 294-298 and C.K. Yeung, Y. Fujioka, H. Hachad, R.H. Levy and N. Isoherranen. Clinical pharmacology & Therapeutics 2011, 89, 105-113