Fig. 1 Chemical structure of 14C-bromfenac sodium *: 14C-labeled position

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Ocular Tissue Distribution in Rabbit after Instillation of Bromfenac Sodium Ophthalmic Solution Mitsuyoshi ISAKA, Katsuhiro INADA, Shuichiro TSUTSUMI*, Megumi FusHIMi*, Atsuhiro INABA*, Yoshio KARASAWA* and Yoshio ESUMI* Research Laboratories, Kobe Creative Center, Senju Pharmaceutical Co., Ltd., Hyogo; *Tokai Research Laboratorieș Daiichi Pure Chemicals Co., Ltd., Ibaraki Summary: The absorption, distribution and metabolism of bromfenac sodium were investigated after single or repeated application of 14C-bromfenac sodium ophthalmic solution to both eyes of male albino rabbits at a dose of 0.1 mg/animal (0.05 mg/50 ƒêl/eye). 1. After single instillation, plasma level of radioactivity reached a maximum of 113.2 ng eq./ml at 30 min and then declined with a half-life of 2.2 hr from 1 hr to 12 hr. The radioactivity levels, in almost half of the ocular tissues, reached the maxima at 30 min after administration. Radioactivity distribution to the corneas was the highest, followed by the anterior sclera and conjunctiva. Radioactivity levels in the lens and vitreous body were the lowest. At 72 hr after administration, radioactivity level in the lens was 7% of the maximum but radioactivity in the other tissues was below the detection limit. 2. During repeated instillation, radioactivity level in plasma was below the detection limit at 24 hr after a single dose, but increased with the number of doses after 7 doses and then reached a steady state by 21 doses. Radioactivity levels in ocular tissues increased with the number of doses except a part of tissues, but then reached a steady state by 21 doses. Radioactivity levels in the lens and posterior sclera after 21 doses were 4.0 and 1.6 times higher than those after a single dose, respectively. Elimination of radioactivity from the plasma and ocular tissues after 21 doses was slightly slower than that after a single dose. 3. Parent compound in the aqueous humor collected at 1, 2 and 4 hr after single instillation accounted for 73.0-79.5% of radioactivity in aqueous humor. Four metabolites, a benzoic acid derivative AHR-11665, formed by oxidation of the carboxymethyl group of bromfenac, its precursor WAY-127039-A-1, and 2-oxy indole derivative AHR-10240 and isatine derivative AHR-11652 formed by intramolecular cyclization were detected. Parent compound in the plasma accounted for 76.7-80.5% of radioactivity in plasma at 1, 2 and 4 hr after single instillation. Unknown metabolites 1RaP1, 1RaP2 and 1RaP3 were detected in addition to the metabolites detected in the aqueous humor. Key words: Bromfenac sodium, Ophthalmic solution, Instillation, Ocular tissue distribution, Rabbit

Fig. 1 Chemical structure of 14C-bromfenac sodium *: 14C-labeled position

Fig. 2 Radioactivity concentration in plasma and blood after single instillation of 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) Data are expressed as the mean values±s.d. of three animals. tut=2.2 hr (plasma, 1-12 hr) AUC=156 ng eq. hr ml-1 (plasma, 0-12 hr), 74.2 ng eq. hr ml -1 (blood, 0-4 hr)

Table I Radioactivity concentration in tissue after single instillation of 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) continued Table I continued Data are expressed as the mean values±s.d. of three animals. N.D. : Not detected

Table II Radioactivity concentration in tissue 24 hr after daily instillation of 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal/day) Data are expressed as the mean values±s.d. of three animals. N.D. : Not detected Table III Radioactivity concentration in tissue after a 21 day period of daily instillation of 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal/day) Data are expressed as the mean values±s.d. of three animals. N.D. : Not detected

Table IV Concentration of bromfenac sodium and its metabolites in plasma after single instillation of 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) Plasma was analyzed by TLC in solvent system; ethyl acetate: methanol: water (77:13:10). Data are expressed as the mean values±s.d. of three animals. Values in parentheses are expressed as percentage of radioactivity in plasma. * : Recovery of radioactivity from plasma through extraction procedure

Fig. 3 Thin-layer chromatograms of bromfenac sodium and its metabolites in plasma after single instillation 14C-bromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) of Solvent system : ethyl acetate: methanol: water (77 : 13 : 10) Authentic samples 失 に つ い て はAzaxanthone誘 導 体 の 抗 ア レル ギ ー 剤 で あ る エ リ ッ ク ス 点 眼 液3) プ ロ ピ オ ン 酸 誘 導 体 pranoprofenを 主 薬 とす る非 ス テ ロ イ ド性 抗 炎 症 剤 で あ られ た ま た 反 復 投 与 期 間 中 の分 布 で は 組 織/血 漿 中 放 射 能 濃 度 比(T/P比)に 大 き な変 化 が な い こ とか ら反 復 投与 に よる特 定 組 織 へ の 蓄積 性 は な く 全 ての 測 定 組 る ニ フ ラ ン点 眼液4) フ マ ル 酸 ケ トチ フ ェン を主 薬 とす 織 が21回 る塩 基 性 抗 ア レル ギ ー 剤 で あ るザ ジ テ ン 点 眼 液5)な どに れ た 21回 投 与 後 の 分 布 は角 膜 結 膜 お よび 前 部 強 膜 お い て も遅 く 種 々の薬 物 で プ ロム フ ェナ ク ナ トリウム に高 く 単 回 投 与 群 とほ ぼ 同様 であ った と同様 の 傾 向 が認 め られて い る 反 復 投 与 後 の 消 失 に つ い て は 最 終 投 与 後168時 蓄積 性 について検討 す るため に 雄性 白色 ウサギ に 0 1mg/anima1で1日1回 間で 血 漿 を 除 く約 半 数 の 組 織 に 低 レベ ル の 放 射 能 が認 め ら 反 復 投 与 した れ そ の 中 で も水 晶体 お よ び肝 臓 で 消失 が遅 か っ た 反 投 与 後 の 血 漿 中放 射 能 濃 度 よ り 復 投 与 後 の 眼球 組 織 か らの 放 射 能 の 消失 は単 回投 与 に比 血 漿 は21回 投 与 ま で に ほ ぼ 定 常 状 態 に な る もの と考 え 較 して緩 慢 で あ っ た もの の 放 射 能 は確 実 に減 少 した こ 1 7 14お よび21回 最 高21回 投 与 ま で に ほ ぼ 定常 状 態 にな る もの と考 え ら

Table V Concentration of bromfenac sodium and its metabolites in aqueous humor after single instillation of 14Cbromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) Aqueous humor was analyzed directly by TLC in solvent system; ethyl acetate: methanol: water (77:13:10). Data are expressed as the mean values ±S.D. of three animals. Values in parentheses are expressed as percentage of radioactivity in aqueous humor. Fig. 4 Thin-layer chromatograms of bromfenac sodium and its metabolites in aqueous humor after single instillation of 14Cbromfenac sodium ophthalmic solution to the eyes of male rabbits (dose: 0.1 mg/animal) Solvent system : ethyl acetate: methanol: water (77 : 13 : 10). : Authentic samples

Scheme 1 Possible metabolic pathway of bromfenac sodium in rabbits

1) Thomas F. Patton and Joseph R. Robinson: Influence of top ical anesthesia on tear dynamics and ocular drug bioavaila bility in albino rabbits. Journal of Pharmaceutical Sciences, 64: 267-271 (1975). 2) Thomas F. Patton and Joseph R. Robinson: Quantitative precorneal disposition of topically applied policarpine ni trate in rabbit eyes. Journal of Pharmaceutical Sciences, 65: 1295-1301 (1976).

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