Complications
The combination of gemfibrozil plus a statin is contraindicated in all people due to an increased risk of myopathy. In patients with GS, this interaction is further accentuated as glucuronidation is an important pathway for the metabolism of some statins and that pathway is compromised in patients with GS. Patients with GS may also have an increased risk of statin intolerance so should be monitored more closely while taking them. If combination fibrate–statin therapy is required, fenofibrate is a safer option than gemfibrozil, but should still be used with caution.[39][40]
Irinotecan is an antineoplastic agent used in the treatment of metastatic colorectal cancer. Hydrolysis of irinotecan leads to formation of SN-38, which is a potent topoisomerase I inhibitor. Glucuronidation of SN-38 is catalyzed by uridine-diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for GS.
Studies have shown reduced levels of SN-38 glucuronide in patients who are homozygous or heterozygous for the (TA)TAA variant allele (UGT1A1*28 polymorphism). This results in a significantly increased risk of toxicity from irinotecan, and screening patients for this UGT1A1 polymorphism is recommended.
Irinotecan should be avoided in patients with GS.[33]
Patients on a protease inhibitor (e.g., atazanavir) or sorafenib in combination with irinotecan can also develop severe irinotecan toxicity.[14][17][18]
There have been concerns that certain drugs may cause adverse effects due to how they interact with the physiology of patients with GS.[14]
Avoiding oral acetaminophen at recommended doses is not currently supported. Studies based on intravenous administration of acetaminophen found reduced glucuronidation of the drug in patients with GS, but no such correlation was found after oral administration.[34][35][36]
The UGT1A1*28 polymorphism may be associated with the development of indirect hyperbilirubinemia in patients with rheumatoid arthritis receiving tocilizumab, a monoclonal antibody to the interleukin-6 receptor. No other evidence of severe liver toxicity has been demonstrated in these patients.[27]
One observation has been made regarding the UGT1A1*28 variant in two patients receiving treatment for hepatitis C with pegylated interferon and ribavirin. The patients may have developed a higher indirect bilirubin level due to ribavirin, when compared with patients who do not carry this variant.[37] However, a subsequent study showed no correlation between the presence of UGT1A1*28 and ribavirin-related adverse effects among patients with chronic hepatitis C.[38]
An increased risk of hyperbilirubinemia has also been identified among patients with GS treated with protease inhibitors, such as atazanavir, and among those treated with the tyrosine kinase inhibitor sorafenib.[14][28]
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