UDP-Glucuronosyltransferase Metabolism in Drug Interactions

UDP-Glucuronosyltransferases (UGTs) constitute a superfamily of phase II drug-metabolising enzymes that catalyse the conjugation of glucuronic acid to a vast array of lipophilic compounds, facilitating their aqueous solubility and excretion. This glucuronidation pathway plays a pivotal role in the clearance of endogenous substrates such as bilirubin and steroid hormones, as well as numerous therapeutic agents spanning anticancer drugs, analgesics, and cardiovascular medications. Variability in UGT expression and activity arises from genetic polymorphisms, age-dependent maturation, disease-related downregulation, and co-administration of inhibitors or inducers. Such variability underpins clinically significant drug–drug interactions (DDIs), where one agent alters the clearance of another via competitive inhibition or enzyme induction. This can lead to altered systemic exposure, reduced efficacy or heightened toxicity. The global significance of UGT-mediated interactions is underscored by their prevalence in polypharmacy settings and their impact on dose optimisation in vulnerable populations, including children, the elderly and patients with hepatic impairment. Advances in structural biology and in vitro–in vivo extrapolation models have improved the prediction of UGT-related DDIs, while pharmacogenomic profiling offers potential for personalised therapy. An integrated understanding of UGT isoform specificity, substrate overlap and regulatory mechanisms is essential to mitigate adverse interactions and to guide safe co-prescription strategies.

Research from Nature Portfolio

Recent studies have characterised the inhibitory profiles of tyrosine kinase inhibitors (TKIs) against key human UGT isoforms, revealing potent competitive inhibition of UGT1A1 and UGT2B17 by lapatinib and imatinib, respectively. Detailed kinetic analyses in hepatic microsomes and recombinant systems quantified inhibition constants (Ki) in the submicromolar range, while pharmacokinetic modelling predicted significant increases in the area under the curve (AUC) of co-administered drugs primarily cleared by these UGTs. These findings have prompted risk assessments for clinically relevant DDIs and recommendations for dose adjustments when TKIs are prescribed alongside UGT substrates. The work exemplifies a rigorous approach to delineate enzyme–inhibitor interactions and to forecast their impact on systemic drug exposure.

UDP-Glucuronosyltransferase Metabolism in Drug Interactions publication trend

The graph below shows the total number of articles in udp-glucuronosyltransferase metabolism in drug interactions across all publications each year (not limited to Nature Index journals).

Technical terms

UDP-Glucuronic Acid: The activated form of glucuronic acid serving as the glucuronide donor in UGT-catalysed reactions.

Glucuronidation: A conjugation reaction attaching glucuronic acid to substrates, increasing their hydrophilicity to facilitate excretion.

Area Under the Curve (AUC): A pharmacokinetic parameter representing total systemic drug exposure over time.

Competitive Inhibition: A mechanism whereby an inhibitor binds to the active site of an enzyme, reducing substrate metabolism.

References

1. Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression. British Journal of Cancer (2020).
2. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.. Journal of Biological Chemistry (1994).
3. Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases. Scientific Reports (2015).
4. Structure and Protein–Protein Interactions of Human UDP-Glucuronosyltransferases. Frontiers in Pharmacology (2016).
5. Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children. Frontiers in Pharmacology (2016).
6. Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors. Archives of Toxicology (2020).