title: Synergistic effect of EDTA and boric acid on corneal penetration of CS-088.
abstract: In order to investigate the effects of EDTA and boric acid (EDTA/boric acid) on the corneal penetration of CS-088, an ophthalmic agent, the apparent permeability coefficient of CS-088 in the presence of EDTA/boric acid across the isolated corneal membranes of rabbits was measured using an in vitro penetration chamber system. FITC-dextran (M.W. 4400) and an electrical method based on membrane resistance were used to provide a quantitative assessment of the enhancing effect of EDTA/boric acid. The corneal penetration of CS-088 was significantly enhanced in the presence of EDTA/boric acid by approximately 1.6-fold. The permeability-enhancing effect of EDTA/boric acid was apparently synergistic and concentration-dependent on both EDTA and boric acid. The penetration of FITC-dextran, a paracellular marker, and electrical resistance of corneal membranes were not affected in the presence of EDTA/boric acid. Furthermore, no enhancing effect of EDTA/boric acid was observed in de-epithelialized corneas, although de-epithelialized corneas exhibited a markedly higher permeability of CS-088 that was 24-fold greater than that for intact corneas. In conclusion, EDTA/boric acid synergistically enhances the transcellular permeability of CS-088 in the outer layer but not in the inner layers of the corneal membrane.
authors.affiliation: Pharmaceutical Development Laboratories, Sankyo Co., Ltd. 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan. tkikuc@sankyo.co.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Kusai
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001888:Boric Acids / Q000494:pharmacology*; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004492:Edetic Acid / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics*; D008297:Male; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D013777:Tetrazoles / Q000493:pharmacokinetics*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001888:Boric Acids; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan; D004492:Edetic Acid; C032688:boric acid