Scientists working in drug metabolism today are adept at deploying new and increasingly sophisticated in vitro methods to study drug metabolism and drug transport and, indeed, have access to a bewildering (to the novice) array of cell-based assays. It is certainly difficult to imagine how drug discovery and development could have proceeded in DMPK without this rich resource of in vitro assays, an era that started in the 1970s. Those who can remember the beginning of the in vitro revolution will recall that at the time it was a very sick child. The reliable preparation of viable hepatocytes was definitely an art, and skilled practitioners were regarded with some awe. Hepatocytes were fragile and rapidly lost their capacity to metabolize drugs via P450-mediated reactions and at that stage cryo-preserved cells were a long way in the future. To all except the true believers in this technology, they seemed of limited use, even though the practical benefits were obvious. However, as the in vitro methods began to prosper, there was a concomitant decline in interest in in vivo techniques, except for fairly defined regulatory purposes, which were now old fashioned and rather less than cutting edge. Indeed they were, but the (continuing) developments in in vitro techniques have not eliminated the need for in vivo studies. After all, a rat is not simply a furry hepatocyte, but a complex assemblage of organs and interacting systems. And it is from that perspective that the Editors invite the readers of Xenobiotica to view this special issue devoted to research on humanised chimeric and genetically modified mice. What is required to advance in vivo techniques are better, more predictive, models that translate accurately to humans in their capacity for drug metabolism and in their responses to drug toxicity. To this end, developments in genetics have resulted in newfound opportunities to modify drug biotransformation systems, eliminating enzymes, or putting in place in the mouse liver a totally human drug metabolising enzyme, or enzymes, right up to the production of “chimeric” animals with mouse hepatocytes replaced with those of human donors.
There are now an increasing number of such models, and these new models are currently associated with an increasing number of publications describing their application, with varying degrees of success, to problems in xenobiotic metabolism and toxicity. It is clear from the Editors’ own experience, and from conversations with other “early adopters” of these new animal models, that many are still at an early stage and much work is still required before they are fully understood and reliable. However, even if more work may be required, the promise, just like that of those early hepatocytes, is clear. It is just possible that work, such as that subject to review, or described here for the first time, represents the first light of a new renaissance in in vivo models of xenobiotic metabolism that, like the mature in vitro models currently in use, will illuminate and inform research in drug metabolism in the twenty-first century.
Declaration of interest
Kristin Samuelsson and Ian D. Wilson are the Guest Editors for this special issue of Xenobiotica. The Guest Editors report no conflicts of interest relating to the content of this preface or the articles within the special issue.