In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption
and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed
the “transport–metabolism interplay”. The current mechanistic understanding for this interplay is first discussed. In the present article,
studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed
in vitro, in situ, in silico, in animals and humans, followed by CYPs–uptake transporters, CYPs–uptake transporters-efflux transporters,
and phase II metabolic enzymes–transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in
conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability
of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between
DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic
variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs
in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g.
nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs
and DTs and to delineate the underlying mechanisms.