The role of glucuronides in DDIs

Paper Pick

UDP-Glucuronosyl transferase mediated drug-drug interactions: An Industry perspective on recommended in vitro studies

Glucuronidated metabolites have long been considered “innocuous” in nature and are considered less relevant in the MIST (Metabolites in Safety Testing) guidelines except in the case of acyl glucuronides. However, there is growing interest in glucuronides as mediators of drug-drug interactions (DDIs). In our Paper Pick for March 2026, we feature an industry perspective on in vitro studies recommended for investigating UDP-glucuronosyltransferase (UGT) mediated DDIs, written by David Stresser and Michael Zientek [1].

The authors stress that whilst most glucuronidation reactions can be recreated in vitro, rates of catalysis are generally underestimated to that observed in vivo, negatively impacting on prediction of clearance in humans. Despite this, DDIs connected to glucuronides are not common, likely due to the relatively high promiscuity across UGTs coupled with their low affinity but high capacity for substrates, and lower induction potential. This means that where metabolism is spread across multiple UGTs, the potential for DDIs is vastly reduced.

Impact of UGT polymorphism

Of interest is the emphasis of the impact of genetic polymorphisms of some UGTs on drug disposition. One particular example highlighted is that of UGT2B17, mRNA of which has a hugely variable expression across different populations. In fact, > 80% of Japanese, 67% of Koreans and up to 15% of Caucasians are completely unable to produce UGT2B17 protein, most commonly due to a 150Kb deletion across the gene. Thus, where clearance of a drug is driven by UGT2B17, there exists a potential for differences in disposition due to genotype.

The first example of withdrawal of a drug from clinical trials due to UGT2B17 polymorphism relates to MK-7246, an antagonist of a chemoattractant receptor on T helper type 2 cells which was being developed for the treatment of respiratory disease [2]. MK-7246 is metabolised predominantly by UGT2B17 to an acyl glucuronide (M3) in both intestines and liver. Other more minor biotransformations involve oxidation and subsequently to an indirect glucuronide.

Although MK-7246 is a substrate for multiple UGTs, it was the high affinity and metabolism of the drug by first pass metabolism by UGT2B17 that caused a large variability in plasma concentrations of the drug across individuals. In the first-in-human study, a 20-fold difference in mean exposure of MK-7246 was observed between subjects carrying at least one UGT2B17*1 allele (*1 being the wildtype) and those with the mutated UGT2B17*2/*2 genotype. This was attributed to the complete absence of UGT2B17 enzyme activity in the subjects with the UGT2B17*2/*2 genotype. The study was complicated by the involvement of enterohepatic recirculation in drug recipients that did efficiently metabolise MK-7246 to M3 due to release of the parent drug by gut bacteria and subsequent reabsorption, thereby prolonging the duration for which the drug remained in the body. The authors of [2] recommended that UGT phenotyping be performed to help rule out serious DDIs or large variability in PK.

In [1], the authors helpfully summarise various considerations around in vitro test systems covering:

• Optimization of in vitro assay conditions
• Enzyme inhibition
• Reaction phenotyping (including Tables 2 and 3 containing substrates and inhibitors of common drug metabolising UGTs)
• Role of oligomerization in UGT metabolic function
• UGT induction
• Enterohepatic recirculation arising from gut produced glucuronidases
• Mechanism based inhibition of CYPs by glucuronides, e.g. CYP2C8 by some acyl glucuronides
• Extrahepatic expression of UGTs e.g. UGT1A9 in kidney and UGT2B17 in gut
• Impact of inhibition of substrate or UDPGA transport to the ER lumen
• Formation of protein adducts by reactive acyl glucuronides
• Inhibition of uptake and efflux transporters by glucuronides

Glucuronides and CYP induction/inhibition

The metabolism of soticlestat (TAK-935) to a major circulating O-glucuronide M3 (TAK-935-G) is highlighted as an example where expression of a CYP other than CYP2C8 is impacted by the glucuronide itself. Soticlestat is an inhibitor of cholesterol 24 hydroxylase (CYP46A1) and anticonvulsant which was discontinued due to reasons unrelated to DDIs. However, as part of clinical trials M3 was discovered to be an inducer of CYP1A2 [3].

In humans, soticlestat is predominately metabolised to M3 as a result of direct glucuronidation at the hydroxy position, largely by UGT2B4 but also by UGT1A9 [4]. M3 is the dominant metabolite in plasma in humans accounting for 93% of radioactivity. The glucuronide circulates at 18-fold higher concentrations that soticlestat itself. The N-oxide metabolite M1, whilst a major circulating metabolite observed in pre-clinical studies, was not quantifiable in the human radiolabelled study.

Since M3 was present at >10% of total drug related material and at >100% parent exposure in human plasma, further work was undertaken to understand any potential DDI liabilities. Soticlestat M3 exhibited no inhibition or induction potency for CYPs and no inhibition potency for UGTs or transporters, except for CYP1A2 induction. Due to the high circulating levels of M3, a weak in vivo interaction was predicted. However, PBPK modelling of any interaction of M3 with other anticonvulsant drugs metabolised by CYP1A2 (fenfluramine and duloxetine) did not indicate any change in CYP1A2 substrate exposure in humans. In vitro experiments were also conducted using commonly co-administered anticonvulsant drugs that are substrates of UGTs. M3 showed no inhibitory effect on the glucuronidation of these drugs, and conversely, these anticonvulsants did not inhibit the glucuronidation of soticlestat. The findings indicated that clinically significant drug–drug interactions are unlikely with the concomitant use of soticlestat and these anticonvulsants.

This example highlights how major circulating glucuronides could contribute to DDIs via other mechanisms, extending beyond the well-recognized examples of CYP2C8 inhibition caused by the acyl glucuronides of gemfibrozil and clopidogrel.

These cases challenge the long-standing perception of glucuronidated metabolites as merely benign clearance products. While clinically significant UGT-mediated DDIs remain relatively uncommon, growing evidence shows that glucuronides can influence drug disposition through a wider range of mechanisms than previously appreciated, including enzyme induction, transporter interactions, and genotype-dependent variability. As highlighted by Stresser and Zientek, continued refinement of in vitro tools and mechanistic understanding will be essential to better anticipate these effects and improve the prediction of UGT-mediated clearance and drug–drug interactions in the clinic.

References