We would like to bring to your attention to a new metabolism tool available online. Lars Olsen et al. have developed a web based platform that predicts potential sites of metabolization. This free tool is the first web service for prediction of CYP-mediated metabolism. Based on a recent publication from Simon E. Ward et al. where they describe the metabolism pathway of a novel clinical AMPA receptor positive modulator, we tested the prediction tool and the result confirmed the potential utility of this application for the prediction of CYP-mediated metabolism.

Patrik Rydberg, David E. Gloriam and Lars Olsen. Bioinformatics 2010, 26, 2988-2989. www.farma.ku.dk/smartcyp

Simon E. Ward et al. J. Med. Chem. 2010, 53, 5801-5812

In a recent article, Dr Angela D. Kerekes et al. described the PK optimization of a potent Aurora inhibitor 1. This compound presents a good PK profile for intravenous delivery but poor oral bioavailability in rats due to rapid metabolism and poor oral absorption. Metabolism studies determine that the compound undergoes N-desethyl and oxidation to generate metabolites 2 and 3.

To improve the PK, the initial strategy was to block N-Alkylation by introduction of fluorine (see compound 4). This modification improved the oral PK in rat but oral PK in monkey was unchanged. In further metabolism studies the failure of the fluorine addition to improve oral PK was attributed to an additional hydroxylation of the arylic position. The introduction of deuterium to that position resulted in a improved oral PK in monkey (see compound 5). This example demontrates that introduction of fluorine and deuterium when possible can be an excellent strategy to improve oral PK.

Angela D. Kerekes et al. J. Med. Chem. 2011 asap

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