EBM Consult

Which UDP-glucuronosyltransferase (UGT) enzymes are most likely to be involved in drug metabolism and cause drug interactions?


  • The cytochrome P450 enzyme (in particular CYP3A4) is clearly the greatest contributor to drug metabolism for most medications.  However, UDP-glucuronosyltransferase (UGT) enzymes are known to be the second greatest contributors to drug metabolism.
  • There are at least eleven known UGT enzymes involved in drug metabolism with UGT2B7 having the greatest number of substrates dependent on its activity, with UGT1A1, UGT1A9 and UGT1A1 following behind in that order.
  • While many drug interactions through the UGT enzymes do not appear to be as significant as those mediated through the CYP450 system the inhibition of UGT2B7 by valproic acid is known to contribute to a life threatening rash when given with lamotrigine (Lamictal®).  In addition, genetic polymorphisms and inhibitors of UGT1A1 (such as atazanavir, gemfibrozil, indinavir) can put patients at risk for irinotecan (Camptosar®) induced bone marrow suppression.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA

Last Reviewed: February 2018


  • The metabolism, distribution and elimination of medications can occur through a number of pathways which can involve the cytochrome P450 (CYP) enzyme system (phase I metabolism), conjugative enzymes such as sulfation and UDP-glucuronosyltransferase (UGT; phase II metabolism), and influx/efflux cell membrane transporters.(1-3)  In addition, it is now known that many medications can be influenced by a combination of these pathways, thus influencing their safety and efficacy profiles as well as the pharmacokinetic profiles of other medications.  To complicate things further, all of these pathways are known to be subject to genetic polymorphisms, which can contribute to the differences in the pharmacokinetic and pharmacodynamic properties of a particular medication.  It is important for the clinician to recognize and appreciate the contribution of these pathways for proper implementation of drug therapy into clinical practice.  

    As it relates to the metabolism of a medication, the CYP450 enzyme system contributes the most, with CYP3A4 being the most common enzyme used in the metabolism of many medications.(1-3)  The second largest contributor to drug metabolism occurs through UGT enzymes.(3)  There are currently eleven different UGT enzymes that are known to contribute to the phase II metabolism of many of the most prescribed medications used in clinical practice.  Fortunately, the number and degree of significance of drug-drug interactions associated through the UGT enzymes are not as problematic when compared to those that rely upon the CYP450 enzyme system.3  Of the eleven UGT enzymes, UGT2B7 appears to contribute to the metabolism of the greatest number of medications.  The presence of UGT2B7 is similar to locations for other enzymes of drug metabolism and includes the intestine, liver and kidney.   Following UGT2B7 in the number medications that are substrates, are UGT1A1, UGT1A9, and UGT1A4.  UGT2B7 is used by up to 35% of medications on the market, followed by UGT1A4 which was used by 20% and UGT1A1 by 15%.(3)

    Therefore, regardless of the perspective of the evaluation of the UGT enzyme system on drug metabolism, UGT2B7 remains to be one of the greatest contributors of drug metabolism for medications that clinicians will likely prescribe, dispense and/or administer to their patients.  In fact, it is the inhibition of UGT2B7 by valproic acid that contributes to the life threatening skin rashes when being coadministered with the anticonvulsant, lamotrigine (Lamictal).4  Since lamotrigine does not have many other metabolic pathways to go through, this drug-drug interaction with valproic acid can significantly compromise the safety of the patient.  Another example of a clinically relevant drug interaction is known to occur with UGT1A1, where known inhibitors of UGT1A1 (such as atazanavir, gemfibrozil, and indinavir) could put the patient taking irinotecan at significant risk for bone marrow suppression since irinotecan is largely dependent on UGT1A1 for its metabolism.(5-7)

    Since many medications have several other UGT enzymes for their metabolism, as well the use of CYP450 enzymes and/or transporters, the inhibition of one UGT enzyme alone generally does not result in clinically relevant drug interactions for some medications.(3)    This does not mean that drug interactions or adverse drug events are not associated with UGT enzymes.  The above examples clearly show that their influence can be clinically significant.


    1. United States Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.  September 2006. Clinical Pharmacology. Accessed last on 5/19/2009.
    2. Ohno Y, Hisaka A, Suzuki H.  General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs.  Clin Pharmacokinet  2007;46:681-96.
    3. Williams AJ, Hyland R, Jones BC et al.  Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.  Drug Metab Dispos  2004;32:1201-8.
    4. Busti AJ, Lehew DS, Nuzum DS, Daves BJ, McKeever GC.  How does valproate (Depakene® or Depakote®) interact with lamotrigine (Lamictal®) to increase the risk of potentially life threatening skin rashes, such as Steven-Johnson Syndrome, when neither one of the drugs are known to be significant substrates or inhibitors of the CYP450 enzyme system?   PW Drug Interact Newsl 2009;1(2):1-4.
    5. Atazanavir sulfate (Reyataz®) product package insert.  Bristol-Meyers Squibb; Princeton, NJ.  April 2009.
    6. Prueksaritanont T, Tang C, Qiu Y et al.  Effects of fibrates on metabolism of statins in human hepatocytes.  Drug Metab Dispos  2002;30:1280-7.
    7. Prueksaritanont T, Zhao JJ, Ma B et al.  Mechanistic studies on metabolic interactions between gemfibrozil and statins.  J Pharmacol Exp Ther  2002;301:1042-51.
    8. National Comprehensive Cancer Network (NCCN).  Guidelines for the treatment of colon cancer.  Last accessed on 1-29-2009.

MESH Terms & Keywords

  • Phase II metabolism, UGT, UDP, Glucuronosyltransferas, UGT Drug Interactions