Ocular and Plasma Pharmacokinetics of Sitagliptin Eye Drops: Preclinical Data

Abstract

Background/Objectives: Early stages of diabetic retinopathy are currently considered an unmet medical need due to the lack of effective treatments beyond proper monitoring and control of glycemia and blood pressure. Sitagliptin eye drops have emerged as a new therapeutic approach against early stages of the disease, as they can prevent its main hallmarks, including both neurodegeneration and microvascular impairment. Interestingly, all of these effects occur without any glycemic systemic improvement. In the present study, we aimed to investigate the pharmacokinetics and distribution of the drug within the eye and plasma. Methods: A total of 48 male New Zealand rabbits were treated with topical administration (eye drops) of sitagliptin at two concentrations: 5 mg/mL and 10 mg/mL. Blood, iris/ciliary body, retina/choroid, aqueous humor, and vitreous humor samples were collected at specific intervals post-administration (10 and 30 min and 1, 3, 6, 15, and 24 h), processed, and analyzed using an LC-MS/MS method. The pharmacokinetics of sitagliptin were then calculated, and statistical comparisons were performed. Results: Our findings indicate that sitagliptin reaches the retina prior to the aqueous and vitreous humors, suggesting that its absorption follows the transscleral route. Additionally, systemic absorption was minimal and below pharmacologically active concentrations. Conclusions: These results support the use of an eye drop formulation for the treatment of diabetic retinopathy and other retinal diseases.

Keywords: diabetic retinopathy; dipeptidyl peptidase-4 inhibitor; eye drops; pharmacokinetics; sitagliptin; transscleral.

Figure 1

Sample weights. Bar graphs illustrate the mean total sample weight measurements for each eye component studied, independently of eye laterality or treatment received. The green bar represents samples from the aqueous humor, the blue bar represents samples from the vitreous humor, the black bar represents samples from the iris/ciliary body, and the red bar represents samples from the retina/choroid. Individual values are indicated by circle symbols. n = 84. *** p < 0.001.

Figure 2

Individual pharmacokinetic analysis of sitagliptin concentrations among the different ocular tissues. (A–D) Temporary profiles of sitagliptin concentrations in the aqueous humor (A), vitreous humor (B), iris/ciliary body (C), and retina/choroid (D) for each dose and eye. A total n of 21 rabbits (3 at each time of extraction) was used for each eye. Symbols illustrate the mean value of the 3 animals at each extraction time, while the error bars represent the standard deviation. The concentration and time axes are presented in a logarithmic base-2 scale format.

Figure 3

Comparison of sitagliptin pharmacokinetic profiles between the four eye matrices studied. (A,B) Sitagliptin measurements (ng/g tissue) in the four studied parts of the eye during the experimental course of rabbits treated with sitagliptin 10 mg/mL (A) or sitagliptin 5 mg/mL (B). The pharmacokinetic profile of the aqueous humor (green circles), vitreous humor (blue circles), iris/ciliary body (black circles), and retina/choroid (red circles). A total n of 21 rabbits (3 at each time of extraction) was used per experimental group. The symbols represent the mean of the 3 animals for each extraction time, while the error bars represent the standard deviation. The concentration and time axes are presented in a logarithmic base-2 scale format. The X axis (time) is presented in a logarithmic base-2 scale format. A statistical analysis was conducted to compare the different concentrations, with the time points displaying significant differences highlighted in the graph on the right (5 mg/mL). * p < 0.05, ** p < 0.01.

Figure 4

Pharmacokinetic profile of sitagliptin bloodstream levels for both tested concentrations. (A) Blood sitagliptin measurements (ng/mL) during the experimental course of rabbits treated with sitagliptin 10 mg/mL (dark blue circles) or sitagliptin 5 mg/mL (light blue circles). A total n of 21 rabbits (3 at each time of extraction) was used per experimental group. The symbols represent the mean of the 3 animals for each extraction time, while the error bars represent the standard deviation (SD). The concentration and time axes are presented in a logarithmic base-2 scale format. (B) Table exhibiting sitagliptin bloodstream concentrations for both groups during the experimental course. Concentrations are expressed as the mean ± SD of 3 animals at each extraction time. n = 21; * p < 0.05, ** p < 0.01.

Figure 5

Scheme showing the transscleral route of sitagliptin eye drops’ absorption. After eye drops are applied and distributed across the tear film, the drug is absorbed through the conjunctiva and then penetrates the sclera via diffusion. Certain factors, such as molecular size and lipophilicity, influence this process, with smaller, lipophilic molecules penetrating more easily. Once through the sclera, the drug reaches the choroid and, subsequently, the retina, where it exerts therapeutic effects.