Understanding the ocular accumulation of mefuparib and its N-dealkylation metabolite: Pharmacokinetics, melanin affinity, and cellular disposition

First report on mefuparib's ocular accumulation via melanin binding. • Mefuparib accumulation in ocular pigment membrane via QWBA. • High melanin affinity drives ocular retention of mefuparib. • Mefuparib shows 58-fold higher eye exposure than M8 in LE rats. Mefuparib, a novel poly (ADP-ribose) polymerase inhibitor (PARP), is primarily utilized for treating various advanced or metastatic malignant tumors. Previous research has indicated that mefuparib-related compounds accumulate notably in the eyes. However, the precise mechanism and components of this accumulation remain unclear. Using quantitative whole-body autoradiography (QWBA), cell uptake and release models, and in vitro melanin binding experiments to explore the accumulation characteristics of mefuparib and its N-dealkylation metabolite M8 in the eye. Results showed the area under the curve (AUC 0-48h ) of mefuparib in Long-Evans (LE) rats was 58.1 times higher than in Sprague-Dawley (SD) rats, with a longer half-life. Conversely, M8 had a lower (AUC 0-48h ) in LE rats. This indicates the main substance accumulated in the eyes is mefuparib, and the accumulation site is the pigment membrane of LE rats. The uptake of mefuparib by Retinal Pigment Epithelium (RPE) cells was 2.81-4.92 times that of Adult Retinal Pigment Epithelial-19 (ARPE-19) cells, and the release within 24 h was only 30.5%. Its melanin binding parameter B max (451 ± 3.15 nmol/mg) was significantly higher than that of M8 (120 ± 6.43 nmol/mg). In conclusion, the high uptake, low release and strong melanin binding capacity of mefuparib jointly lead to its intraocular accumulation, providing data support for the subsequent optimization of compound structure to reduce ocular accumulation or offering new directions for the development of new ocular treatments. Download: Download high-res image (235KB) Download: Download full-size image