Abstract
It is essential to elucidate drug distribution in the ocular tissues and drug transit in the eye for ophthalmic pharmaceutical manufacturers. Atropine is a reversible muscarinic receptor used to treat various diseases. However, its distribution in ocular tissues is still incompletely understood. Matrix-assisted laser desorption/ionization–imaging mass spectrometry (MALDI-IMS) evaluates drug distribution in biological samples. However, there have been few investigations of drug distribution in ocular tissues, including whole-eye segments. In the present study, we explored the spatial distribution of atropine in the whole-eye segment by MALDI-IMS, and then evaluated the changes in atropine level along the anterior–posterior and superior–inferior axes. A 1% atropine solution was administered to a rabbit and after 30 min, its eye was enucleated, sectioned, and analyzed by MALDI-IMS. Atropine accumulated primarily in the tear menisci but was found at substantially lower concentrations in the tissue surrounding the conjunctival sacs. Relative differences in atropine levels between the anterior and posterior regions provided insights into the post-instillation behavior of atropine. Atropine signal intensities differed among corneal layers and between the superior and inferior eyeball regions. Differences in signal intensity among tissues indicated that the drug migrated to the posterior regions via a periocular-scleral route. Line scan analysis elucidated atropine transit from the anterior to the posterior region. This information is useful for atropine delivery in the ocular tissues and indicates that MALDI-IMS is effective for revealing drug distribution in whole-eye sections.
Highlights
Optimization of drug delivery to target ocular tissues remains a challenge for ophthalmic pharmaceutical manufacturers owing to their unique anatomy and physiology
We evaluated the effectiveness of matrix-assisted laser desorption/ionization (MALDI)-Imaging mass spectrometry (IMS) at revealing drug distribution in whole-eye sections
The ultra-high mass resolving power allowed the assignment of the atropine peak [atropine + H]+ at 290.17474 with high mass accuracy and clearly separated from all other peaks
Summary
Optimization of drug delivery to target ocular tissues remains a challenge for ophthalmic pharmaceutical manufacturers owing to their unique anatomy and physiology. Autoradiography (ARG) and drug quantification by high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC-MS) are used to assay drug distribution in ocular tissues. Each of these methods has certain limitations. In HPLC or LC-MS, the eyeball is enucleated and separated into segments including the cornea, conjunctiva, iris/ciliary body, lens, retina, and sclera. The data collected by this method provide little information about the drug distribution within a specific tissue. There is a high risk of analyte contamination when the tissue is separated and harvested because certain tissues (aqueous humor, vitreous body, retina, and choroid) are fluid or brittle
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