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    ๊ณต๋ฌด์› ๋ฐ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๊ฐ€ ์ •๋ถ€์‹ ๋ขฐ์— ๋ฏธ์น˜๋Š” ์˜ํ–ฅ์— ๊ด€ํ•œ ์—ฐ๊ตฌ

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    ํ•™์œ„๋…ผ๋ฌธ (์„์‚ฌ)-- ์„œ์šธ๋Œ€ํ•™๊ต ๋Œ€ํ•™์› : ํ–‰์ •๋Œ€ํ•™์› ํ–‰์ •ํ•™๊ณผ, 2018. 2. ๊น€๋ณ‘์„ญ.๋ณธ ์—ฐ๊ตฌ๋Š” ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๊ฐ€ ์ค‘์•™์ •๋ถ€ ๋ฐ ์ง€๋ฐฉ์ •๋ถ€ ๊ฐ๊ฐ์˜ ์‹ ๋ขฐ์— ๋ฏธ์น˜๋Š” ์˜ํ–ฅ๊ณผ, ๊ทธ ์˜ํ–ฅ๋ ฅ์„ ๋ถ„์„ํ•จ์œผ๋กœ์จ ์ •๋ถ€์‹ ๋ขฐ ์ œ๊ณ ๋ฅผ ์œ„ํ•œ ์‹œ์‚ฌ์ ์„ ๋„์ถœํ•˜๊ณ ์ž ํ•˜์˜€๋‹ค. ๋ถ„์„ํ‹€์„ ๊ตฌ์ถ•ํ•˜๊ธฐ ์œ„ํ•˜์—ฌ ์„ ํ–‰์—ฐ๊ตฌ๋ฅผ ํ†ตํ•ด ์‹ ๋ขฐ ๋ฐ ์ •๋ถ€์‹ ๋ขฐ์˜ ๊ฐœ๋…์ •์˜์™€ ์ •๋ถ€์‹ ๋ขฐ์˜ ์˜ํ–ฅ์š”์ธ์— ๋Œ€ํ•ด ๊ฒ€ํ† ํ•˜์˜€๋‹ค. ํŠนํžˆ ์ •๋ถ€๊ธฐ๊ด€ ๋ฐ ๊ตฌ์„ฑ์› ๋“ฑ ์ธ์ ์š”์ธ ์ธก๋ฉด ๋ฐ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •๋ถ€์‹ ๋ขฐ ๊ฐ„์˜ ๊ด€๊ณ„์— ๋Œ€ํ•œ ์„ ํ–‰์—ฐ๊ตฌ๋ฅผ ๊ฒ€ํ† ํ•˜์—ฌ, ์ •๋ถ€์‹ ๋ขฐ์— ๋Œ€ํ•œ ์˜ํ–ฅ์š”์ธ์œผ๋กœ ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๋กœ ์„ค์ •ํ•˜๋Š” ๋ถ„์„ํ‹€์„ ๊ตฌ์ถ•ํ•˜์˜€๋‹ค. ๋ถ„์„์„ ์œ„ํ•ด 2016๋…„ ํ•œ๊ตญํ–‰์ •์—ฐ๊ตฌ์› ํ–‰์ •์— ๊ด€ํ•œ ๊ตญ๋ฏผ ์ธ์‹์กฐ์‚ฌ ๋ฐ์ดํ„ฐ๋ฅผ ํ™œ์šฉํ•˜์˜€๋‹ค. ๊ทธ๋ฆฌ๊ณ  ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๋ฅผ ๋…๋ฆฝ๋ณ€์ˆ˜๋กœ ์„ค์ •ํ•˜๊ณ , ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์˜ ํ•˜์œ„๋ณ€์ˆ˜๋กœ ์ฒญ๋ ด์„ฑ, ์ฑ…์ž„์„ฑ, ์ „๋ฌธ์„ฑ์„ ์„ค์ •ํ•˜์˜€๋‹ค. ์ข…์†๋ณ€์ˆ˜๋Š” ์ •๋ถ€์‹ ๋ขฐ๋กœ ์„ค์ •ํ•˜๊ณ , ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ๋ฅผ ํ•˜์œ„๋ณ€์ˆ˜๋กœ ๊ตฌ์„ฑํ•˜์˜€๋‹ค. ํ†ต์ œ๋ณ€์ˆ˜๋กœ๋Š” ์ธ๊ตฌ์‚ฌํšŒํ•™์  ์š”์ธ ์ค‘ ์—ฐ๋ น, ์„ฑ๋ณ„, ํ•™๋ ฅ, ๊ฐ€๊ตฌ์†Œ๋“, ์ •์น˜์ด๋…, ๊ฒฐํ˜ผ์—ฌ๋ถ€๋ฅผ ์„ค์ •ํ•˜์˜€๋‹ค. ๊ทธ ํ›„ ์ƒ๊ด€๊ด€๊ณ„๋ถ„์„, ๋‹ค์ค‘ํšŒ๊ท€๋ถ„์„, ๋‹ค์ค‘๊ณต์„ ์„ฑ ์ง„๋‹จ์„ ์‹ค์‹œํ•˜์—ฌ ๋…๋ฆฝ๋ณ€์ˆ˜์™€ ์ข…์†๋ณ€์ˆ˜ ๊ฐ„์˜ ๊ด€๊ณ„๋ฅผ ๋ถ„์„ํ•˜๊ณ , ๋‹ค์ค‘๊ณต์„ ์„ฑ์ด ๋ฌธ์ œ๋˜์ง€ ์•Š์Œ์„ ํ™•์ธํ•˜์˜€๋‹ค. ์—ฐ๊ตฌ๊ฒฐ๊ณผ๋ฅผ ์š”์•ฝํ•˜๋ฉด ๋‹ค์Œ๊ณผ ๊ฐ™๋‹ค. ์ฒซ์งธ, ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€ ์ค‘ ์ฒญ๋ ด์„ฑ๊ณผ ๊ด€๋ จํ•˜์—ฌ, ์ฒญ๋ ด์„ฑ์— ๋Œ€ํ•œ ํ‰๊ฐ€๋Š” ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ ๋ชจ๋‘์— ๊ธ์ •์ ์ธ ์˜ํ–ฅ์„ ๋ฏธ์นœ๋‹ค. ๋‘˜์งธ, ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€ ์ค‘ ์ฑ…์ž„์„ฑ๊ณผ ๊ด€๋ จํ•˜์—ฌ, ์ฑ…์ž„์„ฑ์— ๋Œ€ํ•œ ํ‰๊ฐ€๋Š” ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ ๋ชจ๋‘์— ์œ ์˜๋ฏธํ•œ ์˜ํ–ฅ์„ ๋ฏธ์น˜์ง€ ์•Š๋Š” ๊ฒƒ์œผ๋กœ ๋‚˜ํƒ€๋‚ฌ๋‹ค. ์…‹์งธ, ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€ ์ค‘ ์ „๋ฌธ์„ฑ์— ๋Œ€ํ•œ ํ‰๊ฐ€๋Š” ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์—๋Š” ์œ ์˜๋ฏธํ•œ ์˜ํ–ฅ์„ ๋ฏธ์น˜์ง€ ์•Š์œผ๋‚˜ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ์—๋Š” ๊ธ์ •์ ์ธ ์˜ํ–ฅ์„ ๋ฏธ์นœ๋‹ค๋Š” ๊ฒƒ์„ ํ™•์ธํ•  ์ˆ˜ ์žˆ์—ˆ๋‹ค. ๋„ท์งธ, ์ •๋ถ€๊ฐ€ ์ •์ฑ…์„ ์ž˜ ์ˆ˜ํ–‰ํ•˜๊ณ  ์žˆ๋‹ค๋Š” ํ‰๊ฐ€๋Š” ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ ๋ชจ๋‘์— ๊ธ์ •์ ์ธ ์˜ํ–ฅ์„ ๋ฏธ์ณค๋‹ค. ๋‹ค์„ฏ์งธ, ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€์˜ ์˜ํ–ฅ๋ ฅ๊ณผ ๊ด€๋ จํ•˜์—ฌ ์ค‘์•™์ •๋ถ€์™€ ์ง€๋ฐฉ์ •๋ถ€ ์ˆ˜์ค€ ๋ชจ๋‘์—์„œ ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€ ๋ณด๋‹ค ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๊ฐ€ ์ •๋ถ€์‹ ๋ขฐ์— ๋ฏธ์น˜๋Š” ์˜ํ–ฅ๋ ฅ์ด ๋” ํฌ๋‹ค๋Š” ๊ฒƒ์„ ์•Œ ์ˆ˜ ์žˆ์—ˆ๋‹ค. ์—ฐ๊ตฌ ๊ฒฐ๊ณผ๋ฅผ ํ†ตํ•ด ๋„์ถœํ•œ ์‹œ์‚ฌ์ ์€ ๋‹ค์Œ๊ณผ ๊ฐ™๋‹ค. ์ฒซ์งธ, ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ๊ด€๋ จํ•˜์—ฌ ๋ช‡๋ช‡ ์š”์ธ๋“ค์€ ์ •๋ถ€์‹ ๋ขฐ์— ์˜ํ–ฅ์„ ๋ฏธ์นœ๋‹ค. ๋”ฐ๋ผ์„œ ์ •๋ถ€์‹ ๋ขฐ ์ œ๊ณ ๋ฅผ ์œ„ํ•ด์„œ๋Š” ๊ณต๋ฌด์›์˜ ์ž์งˆ์— ๋Œ€ํ•œ ๊ตญ๋ฏผ๋“ค์˜ ๊ธ์ •์ ์ธ ํ‰๊ฐ€๋ฅผ ํ–ฅ์ƒ์‹œํ‚ฌ ์ˆ˜ ์žˆ๋Š” ์ •์ฑ…์  ๋…ธ๋ ฅ์ด ์š”๊ตฌ๋œ๋‹ค. ๋‘˜์งธ, ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€ ์—ญ์‹œ ์ •๋ถ€์‹ ๋ขฐ์— ์˜ํ–ฅ์„ ๋ฏธ์นœ๋‹ค. ํŠนํžˆ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€๋Š” ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€ ๋ณด๋‹ค ์ •๋ถ€์‹ ๋ขฐ์— ๋ฏธ์น˜๋Š” ์˜ํ–ฅ๋ ฅ์ด ๋” ํฐ ๊ฒƒ์œผ๋กœ ๋‚˜ํƒ€๋‚ฌ๋‹ค. ๋”ฐ๋ผ์„œ ์ •๋ถ€์‹ ๋ขฐ ํ–ฅ์ƒ์„ ์œ„ํ•ด์„œ๋Š” ๋ฌด์—‡๋ณด๋‹ค ์ •๋ถ€์˜ ์ •์ฑ…๋Šฅ๋ ฅ์„ ํ–ฅ์ƒ์‹œ์ผœ ์ •๋ถ€์˜ ์ •์ฑ…์— ๋Œ€ํ•œ ๊ตญ๋ฏผ๋“ค์˜ ํ‰๊ฐ€์™€ ์ธ์‹์„ ๊ธ์ •์ ์œผ๋กœ ์ „ํ™˜์‹œํ‚ค๊ณ ์ž ํ•˜๋Š” ๋…ธ๋ ฅ์ด ์š”๊ตฌ๋œ๋‹ค.์ œ 1 ์žฅ ์„œ๋ก  1 ์ œ 1 ์ ˆ ์—ฐ๊ตฌ์˜ ๋ฐฐ๊ฒฝ ๋ฐ ๋ชฉ์  1 ์ œ 2 ์ ˆ ์—ฐ๊ตฌ์˜ ๋Œ€์ƒ ๋ฐ ๋ฒ”์œ„ 4 ์ œ 2 ์žฅ ์ด๋ก ์  ๋…ผ์˜์™€ ์„ ํ–‰ ์—ฐ๊ตฌ 6 ์ œ 1 ์ ˆ ์ •๋ถ€์‹ ๋ขฐ ๊ด€๋ จ ๋…ผ์˜ 6 1. ์‹ ๋ขฐ์˜ ๊ฐœ๋… 6 2. ์ •๋ถ€์‹ ๋ขฐ์˜ ๊ฐœ๋… 9 3. ์ •๋ถ€์‹ ๋ขฐ์˜ ์ค‘์š”์„ฑ 13 4. ์ •๋ถ€์‹ ๋ขฐ ์˜ํ–ฅ์š”์ธ 14 ์ œ 2 ์ ˆ ์ •๋ถ€์˜ ์ธ์ ์š”์ธ๊ณผ ์ •๋ถ€์‹ ๋ขฐ 19 1. ๋Œ€ํ†ต๋ น ๋ฐ ์ •์น˜์ง€๋„์ž์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •๋ถ€์‹ ๋ขฐ 19 2. ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •๋ถ€์‹ ๋ขฐ 20 3. ๊ธฐ์กด ์—ฐ๊ตฌ์˜ ํ•œ๊ณ„ 26 ์ œ 3 ์ ˆ ์ •์ฑ…์— ๋Œ€ํ•œ ํ‰๊ฐ€์™€ ์ •๋ถ€์‹ ๋ขฐ 27 ์ œ 4 ์ ˆ ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ์˜ ๋น„๊ต 30 ์ œ 3 ์žฅ ์—ฐ๊ตฌ์„ค๊ณ„ 32 ์ œ 1 ์ ˆ ๋ถ„์„ํ‹€ ๋ฐ ์—ฐ๊ตฌ๊ฐ€์„ค 32 1. ์—ฐ๊ตฌ์˜ ๋ถ„์„ํ‹€ 32 2. ์—ฐ๊ตฌ๊ฐ€์„ค 33 ์ œ 2 ์ ˆ ๋ณ€์ˆ˜์˜ ์ธก์ • 36 1. ์ข…์†๋ณ€์ˆ˜ 36 2. ๋…๋ฆฝ๋ณ€์ˆ˜ 37 3. ํ†ต์ œ๋ณ€์ˆ˜ 40 ์ œ 3 ์ ˆ ์—ฐ๊ตฌ์˜ ์ž๋ฃŒ ๋ฐ ํ‘œ๋ณธ์˜ ํŠน์„ฑ 43 ์ œ 4 ์ ˆ ๋ถ„์„๋ฐฉ๋ฒ• 44 ์ œ 4 ์žฅ ๋ถ„์„๊ฒฐ๊ณผ 45 ์ œ 1 ์ ˆ ๊ธฐ์ˆ ํ†ต๊ณ„๋Ÿ‰ ๋ถ„์„ 45 1. ๋…๋ฆฝ๋ณ€์ˆ˜์˜ ๊ธฐ์ˆ ํ†ต๊ณ„๋Ÿ‰ 45 2. ์ข…์†๋ณ€์ˆ˜์˜ ๊ธฐ์ˆ ํ†ต๊ณ„๋ž‘ 47 3. ํ†ต์ œ๋ณ€์ˆ˜์˜ ๊ธฐ์ˆ ํ†ต๊ณ„๋Ÿ‰ 48 ์ œ 2 ์ ˆ. ์ƒ๊ด€๊ด€๊ณ„ ๋ถ„์„ ๊ฒฐ๊ณผ 49 ์ œ 3 ์ ˆ ๋‹ค์ค‘ํšŒ๊ท€๋ถ„์„ ๊ฒฐ๊ณผ 51 1. ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ์ธ์‹ ๋ฐ ์ •์ฑ…ํ‰๊ฐ€์™€ ์ค‘์•™์ •๋ถ€์‹ ๋ขฐ ๊ฐ„์˜ ๊ด€๊ณ„ 52 2. ๊ณต๋ฌด์›์— ๋Œ€ํ•œ ์ธ์‹ ๋ฐ ์ •์ฑ…ํ‰๊ฐ€์™€ ์ง€๋ฐฉ์ •๋ถ€์‹ ๋ขฐ ๊ฐ„์˜ ๊ด€๊ณ„ 53 ์ œ 4 ์ ˆ ๋‹ค์ค‘๊ณต์„ ์„ฑ ์ง„๋‹จ ๊ฒฐ๊ณผ 56 ์ œ 5 ์ ˆ ์—ฐ๊ตฌ๊ฒฐ๊ณผ ์ดํ•ฉ 58 ์ œ 5 ์žฅ ๊ฒฐ๋ก  60 ์ œ 1 ์ ˆ ์—ฐ๊ตฌ๊ฒฐ๊ณผ์˜ ์š”์•ฝ 60 ์ œ 2 ์ ˆ ์—ฐ๊ตฌ์˜ ์‹œ์‚ฌ์  ๋ฐ ์ •์ฑ…์  ํ•จ์˜ 63 ์ œ 3 ์ ˆ ์—ฐ๊ตฌ์˜ ํ•œ๊ณ„ ๋ฐ ํ–ฅํ›„ ์—ฐ๊ตฌ๊ณผ์ œ 64 ์ฐธ ๊ณ  ๋ฌธ ํ—Œ 66 Abstract 72Maste

    Capillary Permeability Model์„ ๋ฐ˜์˜ํ•œ Whole-body PBPK Model์˜ ๊ตฌ์ถ•์— ๊ด€ํ•œ ์—ฐ๊ตฌ

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    ํ•™์œ„๋…ผ๋ฌธ (์„์‚ฌ)-- ์„œ์šธ๋Œ€ํ•™๊ต ๋Œ€ํ•™์› : ์•ฝํ•™๊ณผ, 2015. 2. ์ •์„์žฌ.Whole-body physiologically-based pharmacokinetic (PBPK) model์€ ๊ฐ ์กฐ์ง์œผ๋กœ์˜ ํ˜ˆ๋ฅ˜์†๋„(Qt), ๊ฐ ์กฐ์ง์˜ ๋ถ€ํ”ผ(Vt), ๊ทธ๋ฆฌ๊ณ  ์•ฝ๋ฌผ์˜ tissue-to-plasma concentration ratio(Kp)์˜ ์—ฐ๋ฆฝ๋ฏธ๋ถ„๋ฐฉ์ •์‹ ๋งŒ์œผ๋กœ ์กฐ์ง ๋ฐ ํ˜ˆ์ค‘์˜ ์•ฝ๋ฌผ ๋†๋„๋ฅผ ์˜ˆ์ธกํ•˜๋Š” ์ด๋ก ์ฒด๊ณ„๋ฅผ ๋งํ•œ๋‹ค. ๊ทธ๋Ÿฐ๋ฐ, ์ด ์ด๋ก  ์ฒด๊ณ„๋Š” ์ƒ๋‹นํ•œ ์œ ์šฉ์„ฑ์„ ๊ฐ€์ง์—๋„ ๋ถˆ๊ตฌํ•˜๊ณ  ์กฐ์ง์œผ๋กœ์˜ ์•ฝ๋ฌผ ์ด๋™ ๋‹จ๊ณ„์—์„œ๋Š” ํ•ด๋‹น ์ดํ–‰์˜ ์œจ์† ๋‹จ๊ณ„์— ๋”ฐ๋ผ perfusion rate-limited case ๋˜๋Š” permeability-limited case ์ค‘ ํ•˜๋‚˜๋ฅผ ์‹คํ—˜์ ์œผ๋กœ ์ •ํ•œ ๋‹ค์Œ ์ ์šฉํ•ด์•ผ ํ•˜๋Š” ๋‹จ์ ์ด ์žˆ๋‹ค. ๋”ฐ๋ผ์„œ ์ด ์—ฐ๊ตฌ์˜ ๋ชฉ์ ์€ ์œ„ ๋‘ limiting case๋ฅผ ํ•œ ๊ฐœ์˜ ์ผ๊ด€๋œ ์‹์œผ๋กœ ํ†ตํ•ฉํ•˜์—ฌ whole-body PBPK model๋ฅผ ๋„์ถœํ•˜๋Š” ๊ฒƒ์ด๋‹ค. Capillary permeability model๊ณผ ์œ ์‚ฌํ•œ ๋ฐฉ๋ฒ•์œผ๋กœ rate balance equation์„ ๊ตฌ์ถ•ํ•˜์—ฌ ์–ป์–ด์ง„ ์‹์„ ํ†ตํ•ด, ๊ธฐ์กด์˜ whole-body PBPK model์—์„œ์˜ ๋‘ ๊ฒฝ์šฐ๋ฅผ ํฌ๊ด„ํ•˜๋Š” ํ†ตํ•ฉ๋œ ์‹์„ ์œ ๋„ํ•  ์ˆ˜ ์žˆ์—ˆ๊ณ , ๋˜ํ•œ ์ด ์‹์˜ ์œ ์šฉ์„ฑ์„ ๋†’์ด๊ธฐ ์œ„ํ•ด ํ˜ˆ์•ก๊ณผ ์กฐ์ง ๊ฐ„ interface์˜ ์œ ํšจํ‘œ๋ฉด์ ์„ ํ‰๊ฐ€ํ•˜์˜€๋‹ค. Rat๊ณผ mouse์˜ 9๊ฐœ์˜ ์ฃผ์š” ์žฅ๊ธฐ(๊ฐ„, ๋‡Œ, ์‹ ์žฅ, ์‹ฌ์žฅ, ํ, ๋น„์žฅ, ์žฅ๊ด€, ๊ทผ์œก, ์ง€๋ฐฉ) ๋ฐ carcass์— ๋Œ€ํ•œ ์œ ํšจํ‘œ๋ฉด์ ์ˆ˜์น˜๋ฅผ ์‹คํ—˜์ ์œผ๋กœ ์‚ฐ์ถœํ•˜๊ณ , ์ด ๊ฐ’์„ ์จ์„œ ์—ฌ๋Ÿฌ ์•ฝ๋ฌผ์˜ in vivo plasma ๋ฐ tissue ๋†๋„์˜ ์ถ”์ด๋ฅผ ์˜ˆ์ธกํ•˜๊ณ  ์‹ค์ธก์น˜์™€ ๋น„๊ตํ•˜์˜€๋‹ค. ํŠนํžˆ, ๋ณธ ์—ฐ๊ตฌ์—์„œ๋Š” ์•ฝ๋ฌผ๋™ํƒœํ•™ ์—ฐ๊ตฌ์—์„œ model ์•ฝ๋ฌผ๋กœ ๋„๋ฆฌ ์‚ฌ์šฉ๋˜๊ณ  ์žˆ๋Š” antipyrine์„ model ์•ฝ๋ฌผ๋กœ ์„ ์ •ํ•˜์—ฌ ์‚ฌ์šฉํ•˜์˜€์œผ๋ฉฐ, PAMPA์—์„œ ์ธก์ •ํ•œ permeability ๊ฐ’ ๋ฐ Plasma / tissue์˜ ์•ฝ๋ฌผ์˜ free fraction ์‹ค์ธก์น˜๋ฅผ ์ ์šฉํ•˜์—ฌ ๊ฐ ์กฐ์ง์˜ ์œ ํšจํ‘œ๋ฉด์  ๊ฐ’์„ ๊ณ„์‚ฐํ•  ์ˆ˜ ์žˆ์—ˆ๋‹ค. ๋˜ํ•œ ์ด ์ด๋ก ์„ ์ ์šฉํ•˜์˜€์„ ๋•Œ ์ผ๋ จ์˜ in vitro physicochemical property ๋งŒ์„ ๊ฐ€์ง€๊ณ  ๊ธฐ์กด ์•ฝ๋ฌผ์˜ ์ฒด๋‚ด๋™ํƒœ๋ฅผ ์ƒ๋‹นํžˆ ์ž˜ ๊ณ„์‚ฐํ•ด ๋‚ผ ์ˆ˜ ์žˆ์Œ์„ ์•Œ์•˜์œผ๋ฉฐ ๋”ฐ๋ผ์„œ ๋ณธ ์ด๋ก ์ฒด๊ณ„๋Š” ์ƒ๋‹นํ•œ ์‹ค์šฉ์  ๊ฐ€์น˜๋ฅผ ๊ฐ€์กŒ๋‹ค๊ณ  ํ•  ์ˆ˜ ์žˆ์—ˆ๋‹ค. ๊ถ๊ทน์ ์œผ๋กœ ๋ณธ ์—ฐ๊ตฌ๋ฅผ ํ†ตํ•ด in vitro ์‹คํ—˜๋งŒ์œผ๋กœ ์•ฝ๋ฌผ์˜ in vivo tissue distribution๋ฅผ ์˜ˆ์ธกํ•˜๊ณ  ๋‚˜์•„๊ฐ€ Human-PBPK ์˜ˆ์ธก์ฒด๊ณ„๋กœ ๋ฐœ์ „์‹œํ‚ฌ ์ด๋ก ์  ํ† ๋Œ€๊ฐ€ ๋งˆ๋ จ๋˜์—ˆ๋‹คํ•  ๊ฒƒ์ด๋‹ค.1. Introduction 1 2. Materials and Methods 3 2.1 Model structure 3 2.2 Estimation of surface area 5 2.3 Estimation of trapped volume 7 2.4 Integration plot analysis for allometry 8 2.5 Physiological input parameters 10 2.6 Compound specific input parameters 11 3. Results 12 4. Discussion 18 ์ฐธ๊ณ ๋ฌธํ—Œ 22 Abstract 29Maste
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