Ocular Toxicity of Systemic 5-Fluorouracil Chemotherapy: Role of Lacrimal Gland Transporters

Purpose: 5-Fluorouracil (5-FU) is a commonly used antimetabolite in cancer therapy. Patients (25% to 38%) undergoing chronic systemic 5-FU chemotherapy are affected by ocular toxicity and require cessation of therapy to manage ocular complications. However, the mechanism by which 5-FU crosses the blood-tear barrier is not well understood. The current study investigates the role of organic anion transporters (OAT2 and 3) in the blood-tear barrier of the lacrimal gland, in trafficking 5-FU into the ocular surface. Method: Computer simulations were performed to determine the substrate specificity of 5-FU for OAT isoforms. Tear pharmacokinetic studies of intravenous 5-FU were conducted in rabbits ( n = 3 per group), with and without OAT blockade. The ocular adverse effect of 5-FU was assessed in vitro using human corneal epithelial cells (HCEC). Furthermore, the potential of artificial tears to reduce ocular accumulation of 5-FU was evaluated. Results: Computational studies indicated that 5-FU is a substrate for OAT2. 5-FU was detected in the tear from systemic circulation (C max = 16.7 µg/mL) within five minutes of administration. The concentration of 5-FU reaching the ocular surface reduced HCEC viability in a concentration-dependent manner. Furthermore, topical pretreatment with OAT2 blockers reduced 5-FU exposure in tears by 1.53 to 2.96-fold, and prophylactic artificial tears containing polyethylene glycol 400 and propylene glycol achieved a 1.68-fold reduction in 5-FU exposure in tears. Conclusion: Blocking OAT-2 with eye drops (OAT2 blockers and artificial tears) reduced the tear concentration of 5-FU, suggesting a potential to minimize ocular toxicity of 5-FU in patients undergoing chemotherapy.