Binding of Small Molecule Drugs to Porcine Vitreous Humor

Abstract

Pharmacokinetics in the posterior eye segment has therapeutic implications due to the importance of retinal diseases in ophthalmology. In principle, drug binding to the components of the vitreous, such as proteins, collagen, or glycosaminoglycans, could prolong ocular drug retention and modify levels of pharmacologically active free drug in the posterior eye segment. Since drug binding in the vitreous has been investigated only sparsely, we studied vitreal drug binding of 35 clinical small molecule drugs. Isolated homogenized porcine vitreous and the drugs were placed in a two-compartment dialysis system that was used to separate the bound and unbound drug. Free drug concentrations and binding percentages were quantitated using LC-MS/MS. Drug binding levels varied between 21 and 74% in the fresh vitreous and 0 and 64% in the frozen vitreous. The vitreal binding percentages did not correlate with those in plasma. Our data-based pharmacokinetic simulations suggest that vitreal binding of small molecule drugs has only a modest influence on the AUC of free drug or drug half-life in the vitreous. Therefore, it is likely that vitreal binding is not a major reason for interindividual variability in ocular drug responses or drug-drug interactions.

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

“…Since RHO is the It is worth noting the sustained protective effect after a single injection of both VCP inhibitors. The usual half-life range for small molecules is between 1-10 hours since small lipophilic compounds are cleared rapidly across the blood-ocular barriers to the systemic bloodstream (80)(81)(82). We calculated the expected vitreal half-life for both ML240 and EerI to be approximately 25 minutes, with 98 % being eliminated within 3 hours.…”

Exploring the Impact of Morphology on the Properties of Biodegradable Nanoparticles and Their Diffusion in Complex Biological Medium

“…Mobility studies of nanoparticles in vitreous were performed using porcine eyes ex vivo . 34 To prepare the eyes, they were cleaned from muscles, nerves, and all other undesired tissues. Freshly prepared eyes were briefly dipped into 70% ethanol and then stored in PBS at 4 °C overnight.…”

Diffusion and Protein Corona Formation of Lipid-Based Nanoparticles in the Vitreous Humor: Profiling and Pharmacokinetic Considerations

“…Recently, coadministration of a 40 kDa nanobody with albumin led to a 3-fold increased vitreous half-life in rabbits, 8 whereas protein binding only had a modest influence on the vitreal half-life of 35 small molecule drugs. 9 The extent of intravitreal protein binding on nanoparticles has not been studied, even though the “protein corona” influences the biodistribution of systemic nanoparticles, 10 and the vitreous proteome is more diverse and biologically active than previously known. 11 No studies have been published on the vitreal corona of liposomal systems, which are still the most common types of nanomaterial containing drug products evaluated by the Food and Drug Administration.…”