8cafb8b93c8afcd898d116c3d0a83719 pharmaceuticals-17-01579.pdf 6320bab35c2eba4d54e885f5cc79e5efdf4963ee pharmaceuticals-17-01579.pdf eabd865870fc945b3d07c36e129447e6384bae2faee6dd5e13b86406d5ee6abd pharmaceuticals-17-01579.pdf Title: Ocular and Plasma Pharmacokinetics of Sitagliptin Eye Drops: Preclinical Data Subject: 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: sitagliptin; dipeptidyl peptidase-4 inhibitor; eye drops; transscleral; pharmacokinetics; diabetic retinopathy Author: Cristina Hernández, Hugo Ramos, Anne Létondor and Rafael Simó Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sun Nov 24 10:35:38 2024 CET ModDate: Sun Nov 24 10:42:09 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2488511 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZZTQUO+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 XZDWBH+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 HZEACS+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 ZGGQLO+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 CYVJLM+VnURWPalladioL Type 1 Custom yes yes yes 32 0 CANGEP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 72 0 CANGGA+PalatinoLinotype CID TrueType Identity-H yes yes yes 75 0 CANGGB+PalatinoLinotype TrueType WinAnsi yes yes no 81 0 CANGGD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 84 0 CANGNB+PalatinoLinotype TrueType MacRoman yes yes no 87 0 CANGEP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 103 0 CANGGA+PalatinoLinotype CID TrueType Identity-H yes yes yes 106 0 CANGGB+PalatinoLinotype TrueType WinAnsi yes yes no 112 0 CANGGD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 115 0 CANGNB+PalatinoLinotype TrueType MacRoman yes yes no 118 0 DYUFJK+CMSY10 Type 1 Builtin yes yes yes 128 0 CANGEP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 143 0 CANGGA+PalatinoLinotype CID TrueType Identity-H yes yes yes 146 0 CANGGB+PalatinoLinotype TrueType WinAnsi yes yes no 152 0 CANGGD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 155 0 CANGNB+PalatinoLinotype TrueType MacRoman yes yes no 158 0 CANGEP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 173 0 CANGGA+PalatinoLinotype CID TrueType Identity-H yes yes yes 176 0 CANGGB+PalatinoLinotype TrueType WinAnsi yes yes no 182 0 CANGGD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 185 0 CANGNB+PalatinoLinotype TrueType MacRoman yes yes no 188 0 SMFBJK+PazoMath Type 1 Builtin yes yes yes 195 0 XIRVNA+EURB10 Type 1 Builtin yes yes yes 200 0 CANGEP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 215 0 CANGGA+PalatinoLinotype CID TrueType Identity-H yes yes yes 218 0 CANGGB+PalatinoLinotype TrueType WinAnsi yes yes no 224 0 CANGGD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 227 0 CANGNB+PalatinoLinotype TrueType MacRoman yes yes no 230 0 CAMXTK+EURM10 Type 1 Builtin yes yes yes 240 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-10-15 04:27:15 CEST RepresentationInformation: pharmaceuticals-17-01579.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-10-14 16:41:23 CEST Size: 2488511 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 391 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Sitagliptin Levels Among Ocular Tissues Destination: subsection.2.1 Item: Title: Systemic Absorption of Sitagliptin Eye Drops Destination: subsection.2.2 Item: Title: Pharmacokinetic Evaluation of Sitagliptin Eye Drops Destination: subsection.2.3 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Animals Destination: subsection.4.1 Item: Title: Experimental Groups and Topical Ocular Treatment Destination: subsection.4.2 Item: Title: Anesthesia, Euthanasia, and Sample Processing Destination: subsection.4.3 Item: Title: Protein Precipitation and Mass Spectrometry Destination: subsection.4.4 Item: Title: Statistical Analysis Destination: subsection.4.5 Item: Title: Patents Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Ocular and Plasma Pharmacokinetics of Sitagliptin Eye Drops: Preclinical Data Author: Cristina Hernández, Hugo Ramos, Anne Létondor and Rafael Simó Subject: 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. 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