Background: Mechanistic understanding of the metabolism-transport interplay assumes great importance in
pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies
as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism
is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed
“phase II metabolism-transport interplay”. This interplay is believed to have significant effects on the pharmacokinetics
(bioavailability) of drugs/chemicals undergoing phase II metabolism.
Methods: In this article, we review the studies investigating the phase II metabolism-transport interplay using cell
models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also
summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed.
Results: Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay)
between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II
(conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing
their expression causes the reductions in metabolite excretion, apparent excretion clearance (CLapp
) and total metabolism
), as well as an increase in the intracellular level of metabolite (Ci
). The deconjugation mediated by hydrolase
(acting as a “bridge”) is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and
animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay
thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process
excretion, thus impact of metabolite excretion on its formation is impossible.
Conclusion: Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay.