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Iganidipine, a New Water-Soluble Ca²⁺ Antagonist: Ocular and Periocular Penetration after Instillation

¹From the Eye Clinic, Omiya Red Cross Hospital, Omiya, Japan; the ²Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the ³Department of Ophthalmology, University of Teikyo School of Medicine, Tokyo, Japan; and the ⁴Research Laboratory for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan.

PURPOSE. To evaluate the potential of topical iganidipine ophthalmic solution to exert Ca²⁺-antagonistic activity in the posterior parts of the eye without inducing systemic effects, ocular and periocular penetration of topically instilled iganidipine was studied in pigmented rabbits.

METHOD. First, ¹⁴C-iganidipine solution (0.03%, 30 µL) was instilled into one eye, and vehicle into the other eye to determine the intraocular penetration of iganidipine and to measure the radioactivity of ocular tissues 0.25, 0.5, 1, 2, 4, and 12 hours after a single instillation (n = 3, respectively). Second, iganidipine (0.03%) or betaxolol (0.5%) was unilaterally instilled twice daily for 20 days to study the effects on intravitreously injected various doses of endothelin (ET)-1-induced retinal artery constriction to evaluate whether a pharmacologically active level of the drug penetrated to the posterior retina and to estimate the drug level in the posterior retina (n = 6, respectively). Third, iganidipine (0, 10, or 30 µg/kg: n = 6, 3, and 6, respectively) was intravenously injected to study the effects on intravitreously injected ET-1-induced retinal artery constriction to evaluate iganidipine levels in the posterior retina. Fourth, periocular penetration of iganidipine was studied by means of whole-head autoradiography after a single instillation of ¹⁴C-iganidipine (0.09%, 30 µL; n = 5).

RESULTS. Penetration of topically applied iganidipine to the cornea or aqueous humor was high and estimated to be at least 10 times higher than that reported for timolol or carteolol. Concentrations in the iris-ciliary body or retina-choroid were much higher than in the plasma, both in the treated and control eyes, suggesting that iganidipine binds to uveal pigments. Twice-daily 20-day instillation of iganidipine (0.03%), but not of betaxolol (0.5%), significantly suppressed constriction of the retinal arteries induced by intravitreous injection of ET-1 at a dose of 2.5 or 0.5 ng in the ipsilateral eye. Intravenous injection of iganidipine at a dose of 30 µg/kg (giving a free plasma concentration of approximately 10^-8 M), but not at a dose of 10 µg/kg, significantly suppressed intravitreous ET-1-induced (0.5 ng) constriction of the retinal artery to a similar degree as twice-daily 20-day instillation of 0.03% iganidipine. After a single instillation of 0.09% iganidipine, the equivalent concentration of iganidipine in the ipsilateral retrobulbar periocular space estimated from autoradiography was approximately 3.9 x 10^-8 M between 15 minutes and 1 hour after instillation, consistently higher than in the untreated contralateral eyes by approximately 3.0 x 10^-8 M (P = 0.043).

CONCLUSIONS. In rabbits, topically instilled iganidipine, a Ca²⁺ antagonist, in a 0.03% solution reaches the ipsilateral posterior retina or retrobulbar periocular space by local penetration at concentrations sufficient to act as a Ca²⁺ antagonist.

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