Abstract
Purpose :
Anticancer drugs like Cyclophosphamide (Cyc) cause visual impairment. Drug transporters in the blood-tear barrier can falsely recognize the drugs as substrates and facilitate the entry onto the ocular surface through tear secretion. In our earlier studies, we demonstrated Cyc as Organic cation transporter 1 (OCT1) substrate. We hypothesize that topical formulation containing excipients can be used as OCT1 blockers to prevent the entry of systemic drugs into the eye. The current study aims to evaluate the potential of various excipients to block the uptake of anticancer drugs through OCT1 using in vitro and in vivo studies.
Methods :
In vitro uptake studies were performed in transiently human OCT1 transfected HEK293 cells. DAPI (OCT1 substrate) uptake was performed in the presence of excipients such as Tween20 (T20), Poloxamer407 (P407), Triton-X, and PVPK30 to understand the potential of excipients to block the OCT1. The inhibitory potential was determined by calculating the percentage uptake. In vivo tear kinetics of intravenously administered Cyc was performed in presence and absence of topically administered excipients. Tear was collected using Schirmer strip and drug was analyzed by Liquid Chromatography Mass Spectrometry.
Results :
The in vitro uptake studies showed that T20 and P407 could block the OCT1 transporter with IC50 values 2.26 ± 0.82 µM and 1.41 ± 0.23 mM, respectively. In vivo tear kinetics indicated a higher Cyc concentration in the control group compared to the topical excipients treated group. The AUC(0-2h) of Cyc was 2-fold less in the T20 (109.90 µmol/ml*h) and 1.7-fold less in the P407 (122.17 µmol/ml*h) pre-treated group compared to the control group (212.93 µmol/ml*h). Data is represented as mean ± SEM.
Conclusions :
Of the tested excipients, T20 and P407 inhibited the OCT1 uptake with the highest efficiency. However, P407 showed nearly 700-fold higher IC50 value than T20, indicating T20 as a potential OCT1 blocker. When administered intravenously, the tear concentration of Cyclophosphamide was reduced in the presence of topical excipients. It can be concluded that excipients can be used locally to block the uptake transporters in the lacrimal gland and ocular surface, preventing the anticancer drug entry into the eye and thereby reducing ocular toxicity. However, the effect of blocking the transporters on the transport of endogenous molecules needs to be further elucidated.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.