Isobe Tomoyuki, Kasai Taku, Kawai Hiroyuki
1 Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo, Japan .
2 Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan .
J Ocul Pharmacol Ther. 2016 Sep;32(7):405-14. doi: 10.1089/jop.2016.0028. Epub 2016 Jul 27.
We evaluated the ocular pharmacokinetics of ripasudil (K-115), a selective Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, following topical administration to rabbits.
We determined the ocular distribution of [(14)C]ripasudil by whole-head autoradiography and the radioactivity of each ocular tissue after single and multiple instillation of [(14)C]ripasudil to pigmented rabbits. We also measured the aqueous humor concentrations after concomitant instillation of ripasudil and a combination agent (0.005% latanoprost and 0.5% timolol) to pigmented rabbits as well as the tear fluid concentrations after instillation into rabbits, dogs, and monkeys using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Membrane permeability was evaluated using an in vitro parallel artificial membrane permeability assay system and Ussing chamber with rabbit cornea and conjunctiva.
[(14)C]Ripasudil was rapidly absorbed into the cornea and distributed throughout the eye after topical instillation. The melanin-containing ocular tissues, such as the iris-ciliary body and retina-choroid, showed much higher concentrations of radioactivity than the other nonpigmented tissues. Concomitant instillation showed minor effects on the aqueous humor concentrations of each compound in rabbits. Membrane permeability of ripasudil was higher than other glaucoma drugs in vitro and ex vivo. The aqueous humor concentrations of ripasudil in rabbits were higher than those in dogs and monkeys in the early period after instillation and associated with tear turnover rate.
These results indicate favorable intraocular penetration characteristics of ripasudil following topical administration.
我们评估了选择性Rho相关卷曲螺旋蛋白激酶（ROCK）抑制剂ripasudil（K-115）对兔局部给药后的眼药代动力学。
通过全脑放射自显影测定[(14)C]ripasudil在兔眼中的分布，并在向有色兔单次和多次滴注[(14)C]ripasudil后测定各眼组织的放射性。我们还使用液相色谱-串联质谱法（LC-MS/MS）测定了向有色兔同时滴注ripasudil和联合制剂（0.005%拉坦前列素和0.5%噻吗洛尔）后的房水浓度，以及向兔、狗和猴滴注后的泪液浓度。使用体外平行人工膜通透性测定系统和兔角膜及结膜的Ussing小室评估膜通透性。
局部滴注后，[(14)C]ripasudil迅速被角膜吸收并分布于全眼。含黑色素的眼组织，如虹膜睫状体和视网膜脉络膜，显示出比其他无色素组织更高的放射性浓度。同时滴注对兔眼中各化合物的房水浓度影响较小。ripasudil的膜通透性在体外和体内均高于其他青光眼药物。ripasudil在兔眼中的房水浓度在滴注后的早期高于狗和猴，且与泪液周转率相关。
这些结果表明ripasudil局部给药后具有良好的眼内渗透特性。
