SN38G

SN38G, or SN-38 glucuronide, is the glucuronide conjugate of SN-38, the active metabolite of the chemotherapy drug irinotecan. Irinotecan is a prodrug that is converted to SN-38 by carboxylesterases in the liver and intestines. SN-38 exerts cytotoxic effects by inhibiting topoisomerase I, leading to DNA damage in rapidly dividing cells.

SN-38G is formed from SN-38 through glucuronidation, primarily by UDP-glucuronosyltransferase enzymes, with UGT1A1 Accounts for a major portion of this activity, though other UGTs can contribute. SN-38G is considered an inactivated metabolite and is mainly excreted via bile and urine. It typically has reduced cytotoxic activity compared with SN-38 and serves as a circulating reservoir for potential reconversion to active drug in certain biological compartments.

In the gut, bacterial beta-glucuronidases can hydrolyze SN-38G back to SN-38, releasing active drug within the intestinal lumen. This enterohepatic recirculation can prolong exposure to SN-38 in the gastrointestinal tract and is linked to irinotecan-induced diarrhea and mucosal injury. Systemic exposure to SN-38 is influenced by an individual’s glucuronidation capacity; for example, reduced UGT1A1 activity (such as in UGT1A1 polymorphisms like *28) can raise SN-38 and SN-38G levels, increasing toxicity risk.

SN38G itself is not the primary anticancer agent, but its formation and potential reconversion in the gut are important factors in the pharmacokinetics, efficacy, and adverse-effect profile of irinotecan-based therapy. Research includes approaches to limit gut deconjugation and to personalize dosing based on glucuronidation capacity.