The enzymology of drug metabolism has advanced considerably in the last 20 years, with the advent of molecular biology techniques that have provided detailed sequence information upon which to base rational nomenclature systems, and recombinant enzymes essential to the detailed study of enzyme-ligand interactions. Indeed, contemporary drug discovery and development rely heavily on this advancing lexicon of information to ensure that preclinical drug candidates are chosen with appropriate metabolic stabilities and interaction liability characteristics. Central to these activities is the identification of the specific enzymes involved in the metabolic clearance of a new chemical entity, a process which reaches its zenith for the P450s, due to the wealth of specific substrates, inhibitors, and recombinant enzymes that exist. The increasing availability of crystal structures for human P450s is also propelling efforts to understand and predict P450-ligand interactions in silico. However, impediments to the full implementation of such P450 modeling approaches include the relative dearth of structures with isoform-specific ligands bound and the demonstrated elasticity of mammalian P450 active sites, and research to address these issues will likely be priority items for the future. Much larger knowledge gaps exist for some of the other drug-metabolizing enzymes, notably the reductases, CESs, and glucuronyltransferases, where few isoform-specific substrates and inhibitors are available and recombinant human enzymes are only widely available for the human UGTs. In the case of the reductases, a systematic understanding of the basic enzymology of xenobiotic reduction is still in its infancy. These are important considerations because non-P450 clearance pathways are increasingly emphasized in drug development in order to avoid or minimize drug-drug and drug-gene interactions. Even with a more complete toolbox for the non-P450 enzymes, a much better appreciation of individual tissue isoform concentrations (as opposed to mRNA) will be needed to progress towards realistic scaling of in vitro data to the in vivo situation. While incomplete, experience and advances within the P450 field can serve as a useful template for developing experimental strategies to integrate better non-P450 enzymology into drug development.
Was this article helpful?