The final
therapeutic effect of a
drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of at least one
element of ADME may result in serious drug resistance. In this work we described the role of one
element of this resistance: phase II metabolism with
UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the
ABC transporters, MDR1, MRP and BCRP, than the native
drug. UGT-mediated drug resistance can be associated with (i) inherent overexpression of the
enzyme, named intrinsic drug resistance or (ii) induced expression of the
enzyme, named acquired drug resistance observed when
enzyme expression is induced by the
drug or other factors, as food-derived compounds. Very often this induction occurs via
ligand binding receptors including AhR (
aryl hydrocarbon receptor) PXR (
pregnane X receptor), or other
transcription factors. The effect of UGT dependent resistance is strengthened by coordinate action and also a coordinate regulation of the expression of UGTs and
ABC transporters. This coupling of UGT and
multidrug resistance proteins has been intensively studied, particularly in the case of antitumor treatment, when this resistance is "improved" by differences in UGT expression between
tumor and healthy tissue. Multidrug resistance coordinated with glucuronidation has also been described here for drugs used in the management of
epilepsy,
psychiatric diseases,
HIV infections,
hypertension and
hypercholesterolemia. Proposals to reverse UGT-mediated drug resistance should consider the endogenous functions of UGT.