What is the impact of a mutation in UGT1A1 on drug metabolism?

A mutation in the UGT1A1 gene primarily affects the metabolism of certain drugs, particularly those that require glucuronidation for elimination. UGT1A1 encodes a key enzyme that facilitates the conjugation of bilirubin and various drugs to glucuronic acid, thus making them more water-soluble and easier to excrete.

Irinotecan, a chemotherapy drug used primarily to treat colorectal cancer, is one of the substances that is significantly affected by UGT1A1 activity. In individuals with mutations in UGT1A1, there can be reduced activity of the enzyme, leading to decreased metabolism and elimination of irinotecan. This can cause increased exposure to the active metabolite of irinotecan, SN-38, which can result in heightened toxicity and increased side effects in patients with UGT1A1 polymorphisms, particularly in those with the *28/*28 genotype that results in Gilbert's syndrome.

Understanding the role of UGT1A1 in drug metabolism is crucial for personalized medicine, as it can help determine appropriate dosing strategies and improve patient outcomes by reducing adverse effects associated with chemotherapy. This clear association highlights why the mutation significantly impacts the metabolism of irinotecan.