高脂溶性薬物の体内動態に対する体脂肪減少の影響評価

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Title

高脂溶性薬物の体内動態に対する体脂肪減少の影響評価( 本

_{文(Fulltext) )}

Author(s)

後藤, 昭彦

Report No.(Doctoral

Degree)

博士(獣医学) 乙第158号

Issue Date

2018-03-13

Type

博士論文

Version

ETD

URL

http://hdl.handle.net/20.500.12099/75237

※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。

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㧗⬡⁐ᛶ⸆≀ࡢయෆືែ࡟ᑐࡍࡿ

య⬡⫫ῶᑡࡢᙳ㡪ホ౯

㸰㸮㸯㸵ᖺ

ᒱ㜧኱Ꮫ኱Ꮫ㝔㐃ྜ⋇་Ꮫ◊✲⛉

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㧗⬡⁐ᛶ⸆≀ࡢయෆືែ࡟ᑐࡍࡿ

య⬡⫫ῶᑡࡢᙳ㡪ホ౯

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┠

┠ḟ

␎ㄒ ... 1 ➨1 ❶ ⥴ゝ ... 3 ࡣࡌࡵ࡟ ... 3 1.1 ᮏ◊✲ࡢ┠ⓗ ... 3 1.2 㧗⬡⁐ᛶ⸆≀ࡢ୍⯡ⓗ࡞⸆≀ືែᏛⓗ≉ᛶ ... 4 1.3 1.3.1 ⤌⧊ศᕸ࡟ࡘ࠸࡚ ... 4 1.3.2 ᾘኻ࡟ࡘ࠸࡚ ... 5 1.3.3 ⤒ཱྀ྾཰࡟ࡘ࠸࡚ ... 5 TAK-357 ࡟ࡘ࠸࡚ ... 6 1.4 1.4.1 ≀⌮໬Ꮫⓗᛶ㉁ ... 6 1.4.2 ᢠ࢔ࣝࢶࣁ࢖࣐࣮⑓⸆ࡢ⌧≧࡜ TAK-357 ࡢ⸆⌮స⏝ ... 6 ➨2 ❶ TAK-357 ࡢࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾ࡅࡿయෆືែ ... 7 ࡣࡌࡵ࡟ ... 7 2.1 ᐇ㦂ᮦᩱ࡜᪉ἲ ... 7 2.2 2.2.1 ⿕㦂≀㉁㸪ヨ⸆ ... 7 2.2.2 ື≀... 7 2.2.3 ⿕㦂≀㉁ࡢᢞ୚࠾ࡼࡧ⏕యヨᩱࡢ᥇ྲྀ ... 8 2.2.4 ⾑₢⺮ⓑ⤖ྜ࠾ࡼࡧ⾑⌫⛣⾜ ... 9 2.2.5 ᨺᑕ⬟ࡢ ᐃ ... 9 2.2.6 ⾑₢୰ TAK-357 ࡢᐃ㔞 ... 10 2.2.7 ࢹ࣮ࢱฎ⌮ ... 11 ⤖ᯝ ... 11 2.3 2.3.1 ࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾ࡅࡿᮍኚ໬యࡢ⾑₢୰ືែ ... 11

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2.3.2 ⤌⧊ศᕸ ... 11 2.3.3 ⾑⌫⛣⾜ ... 12 2.3.4 ⾑₢⺮ⓑ⤖ྜ ... 12 2.3.5 ⾑₢୰⤌ᡂ ... 12 2.3.6 ᤼ἥ࠾ࡼࡧ᤼ἥ≀୰⤌ᡂ ... 13 ⪃ᐹ ... 13 2.4 ᑠᣓ ... 16 2.5 ➨3 ❶ ⬡⫫⤌⧊࡬㧗⃰ᗘศᕸࡍࡿ⸆≀ࡢయෆືែ࡟୚࠼ࡿᛴ⃭࡞య㔜పୗࡢᙳ㡪: ⏕⌮Ꮫⓗ⸆≀ື ែ (PBPK) ࣔࢹࣜࣥࢢ&ࢩ࣑࣮ࣗࣞࢩࣙࣥ ... 17 ࡣࡌࡵ࡟ ... 17 3.1 ᐇ㦂ᮦᩱ࡜᪉ἲ ... 17 3.2 3.2.1 ⿕㦂≀㉁㸪ヨ⸆ ... 17 3.2.2 ື≀... 18 3.2.3 ື≀ヨ㦂 ... 18 3.2.4 ⾑₢୰ TAK-357 ࡢᐃ㔞 ... 18 3.2.5 PBPK ࣔࢹࣜࣥࢢ ... 19 3.2.6 ࢩ࣑࣮ࣗࣞࢩࣙࣥ ... 21 ⤖ᯝ ... 22 3.3 3.3.1 ື≀ᐇ㦂 ... 22 3.3.2 PBPK ࣔࢹࣜࣥࢢ ... 22 3.3.3 ࢩ࣑࣮ࣗࣞࢩࣙࣥ ... 22 ⪃ᐹ ... 23 3.4 ᑠᣓ ... 26 3.5 ➨4 ❶ 㧗⃰ᗘ⬡⫫࡬ศᕸࡍࡿ⸆≀ࡢືែ࡟୚࠼ࡿయ⬡⫫ኚ໬ࡢᙳ㡪 ... 27

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ࡣࡌࡵ࡟ ... 27 4.1 ᐇ㦂ᮦᩱ࡜᪉ἲ ... 27 4.2 4.2.1 ⿕㦂≀㉁㸪ヨ⸆ ... 27 4.2.2 ື≀... 28 4.2.3 ື≀ᐇ㦂 ... 28 4.2.4 ⾑₢⺮ⓑ⤖ྜ ... 29 4.2.5 ⃰ᗘ ᐃἲ ... 29 4.2.6 ⸆≀ືែゎᯒ ... 30 4.2.7 ࢩ࣑࣮ࣗࣞࢩࣙࣥ ... 31 ⤖ᯝ ... 32 4.3 4.3.1 ᐇ㦂ࢹ࣮ࢱ ... 32 4.3.2 PBPK ࣔࢹࣜࣥࢢ ... 33 4.3.3 ࢩ࣑࣮ࣗࣞࢩࣙࣥ ... 33 ⪃ᐹ ... 33 4.4 ᑠᣓ ... 36 4.5 ➨5 ❶ ⥲ྜ⪃ᐹ࠾ࡼࡧࡲ࡜ࡵ... 37 TAK-357 ࡢࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾ࡅࡿ⸆≀ືែᏛⓗ≉ᚩ࠾ࡼࡧ⾑₢୰⃰ᗘୖ᪼࡟ᑐࡍࡿᐃᛶⓗ᥎ᐃ .... 37 5.1 ࢖ࢾ TK ヨ㦂᫬࡟ㄆࡵࡽࢀࡓ⾑₢୰⃰ᗘୖ᪼ࡢᐃ㔞ⓗཎᅉ᥎ᐃ ... 38 5.2 ⬡⫫㔞ኚ໬ࡀ㧗⬡⁐ᛶ⸆≀ࡢయෆືែ࡟୚࠼ࡿᙳ㡪࠾ࡼࡧᢞ୚㔞ㄪᩚࡢᚲせᛶ ... 39 5.3 ࡲ࡜ࡵ ... 40 5.4 ㅰ㎡ ... 41 ᘬ⏝ᩥ⊩ ... 42 ᅗ (➨ 1 ❶) ... 50 ᅗ⾲ (➨ 2 ❶) ... 51

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ᅗ⾲ (➨ 3 ❶) ... 61 ᅗ⾲ (➨ 4 ❶) ... 69

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␎

␎ㄒ

ᮏᩥཬࡧᅗ⾲࡛⏝࠸ࡓ␎ㄒࡣ௨ୗࡢ㏻ࡾ࡛࠶ࡿࠋ 6-CB: 2,2',4,4',5,5'-hexachlorobiphenyl

A : amyloid (࢔࣑ࣟ࢖ࢻ )

ADME: absorption, distribution, metabolism and excretion (྾཰㸪ศᕸ㸪௦ㅰ㸪᤼ἥ) AGP: 1-acid glycoprotein ( 1㓟ᛶ⢾⺮ⓑ)

AUC: Area Under the concentration-time Curve (⸆≀⃰ᗘ᫬㛫᭤⥺ୗ㠃✚) BA: bioavailability (ࣂ࢖࢜࢔࣋࢖ࣛࣅࣜࢸ࢕)

BDDCS: Biopharmaceutics Drug Disposition Classification System CLint: intrinsic clearance (⫢ᅛ᭷ࢡࣜ࢔ࣛࣥࢫ)

CLp: total body clearance (඲㌟ࢡࣜ࢔ࣛࣥࢫ) Cmax: maximum concentration (᭱㧗⾑₢୰⃰ᗘ) Ctrough: trough concentration (ࢺࣛࣇ⃰ᗘ) CYP: cytochrome P450 (ࢳࣟࢡ࣮࣒ࣟ P450) DIF: diffusion rate constant (ᣑᩓ㏿ᗘᐃᩘ) FOCE: first-order conditional estimation GFR: glomerular filtration rate (⣒⌫యࢁ㐣㔞)

HPLC: high performance liquid chromatography (㧗㏿ᾮయࢡ࣐ࣟࢺࢢࣛࣇ࢕࣮) HSA: human serum albumin (ࣄࢺ⾑Ύ࢔ࣝࣈ࣑ࣥ)

IACUC: institutional animal care and use committee Ka: absorption rate constant (྾཰㏿ᗘᐃᩘ)

logD: octanol to water partition coefficient (࢜ࢡࢱࣀ࣮ࣝ/Ỉศ㓄ಀᩘ) LSC: liquid scintillation counter (ᾮయࢩࣥࢳ࣮ࣞࢩࣙࣥ࢝࢘ࣥࢱ࣮) MATE: multidrug and toxin extrusion

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MRM: multiple reaction monitoring NMDA: N-methyl-d-aspartate

PBPK model: physiologically-based pharmacokinetic model (⏕⌮Ꮫⓗ⸆≀ືែࣔࢹࣝ) PCBs: poly chlorinated biphenyls (࣏ࣜሷ໬ࣅࣇ࢙ࢽࣝ)

PCDDs: polychlorinated dibenzo-p-dioxins (࣏ࣜሷ໬ࢪ࣋ࣥࢰ-p-ࢪ࢜࢟ࢩࣥ) PK: pharmacokinetics (⸆≀ືែ)

pKa: logarithmic acid dissociation constant (㓟ゎ㞳ᣦᩘ) PK/PD: pharmacokinetics/pharmacodynamics

Px: tissue to blood partition coefficient (⤌⧊⾑ᾮศ㓄ಀᩘ) t1/2: half-life (༙ῶᮇ)

TAK-357: 1-(4-methoxyphenyl)-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran- 5-yl)piperazine TK: toxicokinetics (ࢺ࢟ࢩࢥ࢟ࢿࢸ࢕ࢡࢫ)

TK/TD: toxicokinetics/toxicodynamics Tmax: time to reach Cmax (Cmax ࡟㐩ࡍࡿ᫬㛫)

Vss: distribution volume at steady-state (ᐃᖖ≧ែ࡟࠾ࡅࡿศᕸᐜ✚) Vx: tissue or blood volumes (⤌⧊ᐜ㔞)

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⥴ゝ

➨

1❶

ࡣࡌࡵ࡟ 1.1 ་⸆ရࡢ㛤Ⓨ࡟࠾࠸࡚⸆≀ືែᏛⓗホ౯ࡣᚲ㡲ࡢࡶࡢ࡛࠶ࡾ㸪㠀⮫ᗋヨ㦂࠾ࡼࡧ⮫ᗋヨ㦂࡟࠾࠸ ࡚ᐇ᪋ࡉࢀ࡚࠸ࡿࠋ⸆≀ࡢຠᯝ࠾ࡼࡧ๪స⏝ࡣࡑࡢ⾑₢୰⃰ᗘ㸪ࡲࡓࡣ⤌⧊୰⃰ᗘ࡜῝ࡃ㛵ࢃࡗ࡚࠸ ࡿࠋ⸆≀ືែᏛࡣ྾཰㸪ศᕸ㸪௦ㅰ㸪᤼ἥ (ADME) ࢆᢕᥱࡍࡿࡇ࡜࡟ࡼࡾ㸪ᢞ୚㔞࡜⸆⌮ຠᯝࡢ㛵 ಀ㸪࠾ࡼࡧᢞ୚㔞࡜๪స⏝ࡢ㛵ಀࢆ⪃ᐹࡍࡿ㝿࡟㔜せ࡞᝟ሗ࡜࡞ࡿ (57)ࠋ㏆ᖺ࡛ࡣ⸆≀⃰ᗘ࡜⸆ຠ ཪࡣ๪స⏝ࡢ㛵ಀࢆᐃ㔞ⓗ࡟ゎᯒ࡟ࡍࡿPharmacokinetics/Pharmacodynamics (PK/PD) ゎᯒࡸ Toxicokinetics/Toxicodynamics (TK/TD) ゎᯒࢆ⏝࠸ࡿࡇ࡜࡟ࡼࡾ⏝ἲ⏝㔞࡞࡝ࢆຠ⋡ⓗ࠿ࡘ㐺ษ࡟タ ᐃࡋ㸪◊✲㛤Ⓨࢆ㐍ࡵ࡚࠸ࡃࡇ࡜ࡀ᥎㐍ࡉࢀ࡚࠸ࡿ (40)ࠋࡇࢀࡽࡢᐃ㔞ⓗ࡞ゎᯒࢆࡍࡿ࡟࠶ࡓࡗ࡚ ࡶADME ホ౯ࢆ⾜࠸㸪ヲ⣽࡞యෆືែࢆホ౯ࢆࡍࡿࡇ࡜ࡣ㠀ᖖ࡟㔜せ࡛࠶ࡿࠋࡶࡋ㸪⮫ᗋ࡟࠾࠸࡚ ⸆≀ືែᏛⓗ┦஫స⏝ࡸಶయ㛫ᕪ㸪ࡑࡢ௚⸆≀⃰ᗘኚ໬ࢆᘬࡁ㉳ࡇࡍせᅉࡀ࠶ࡿሙྜ࡟ࡣ๪స⏝ᅇ㑊 ࡸ⸆ຠⓎ⌧ࡢࡓࡵ࡟ᢞ୚㔞ࢆㄪᩚࡍࡿᚲせࡀ࠶ࡿࠋ ᮏ◊✲ࡢ┠ⓗ 1.2 Ṋ⏣⸆ရᕤᴗᰴᘧ఍♫࡟࠾࠸࡚ぢฟࡉࢀࡓ᪂つ࢔ࣝࢶࣁ࢖࣐࣮἞⒪⸆ೃ⿵TAK-357 ࡟ࡘ࠸࡚㸪4 㐌㛫ᅇ᚟ᮇ㛫ホ౯ࢆేࡏࡓ࢖ࢾ1᪥1ᅇ2㐌㛫཯᚟⤒ཱྀᢞ୚ࢺ࢟ࢩࢥ࢟ࢿࢸ࢕ࢡࢫ (TK) ヨ㦂ࢆᐇ᪋ ࡋࡓ࡜ࡇࢁ㸪2 ༉ࡢ㞝ᛶ࢖ࢾࡢ࠺ࡕ 1 ༉࡟࠾࠸࡚᭱⤊ᢞ୚ 2 㐌㛫ᚋ࠿ࡽ㸪ᦤ㣵㔞ࡸయ㔜ࡢపୗࢆక࠺ ⾶ᙅࡀㄆࡵࡽࢀࡓࠋࡇࡢື≀࡟࠾࠸࡚㸪ᦤ㣵㔞ࡸయ㔜ࡢపୗࢆక࠺⾶ᙅࡀㄆࡵࡽࢀࡓ᭱⤊ᢞ୚2 㐌㛫 ᚋ࠿ࡽ㸪TAK-357 ⾑₢୰⃰ᗘୖ᪼ࡀㄆࡵࡽࢀࡓ (ヲ⣽ࡣ➨ 3 ❶࡟グ㍕)ࠋ␗ᖖ࡞⾑₢୰⸆≀⃰ᗘୖ᪼ ࡣᏳ඲ᛶࡢᠱᛕࢆច㉳ࡍࡿࠋࡶࡋ⮫ᗋ࡟࠾࠸࡚ᢞ⸆࡟㉳ᅉࡋ࡞࠸ணᮇࡏࡠ⾑₢୰⃰ᗘୖ᪼ࡀ㉳ࡇࡿྍ ⬟ᛶࡀ࠶ࡾ㸪ࡉࡽ࡟ࡑࡢ⸆≀ࡢᏳ඲ᇦࡀ⊃࠸ሙྜ㸪Ᏻ඲ᛶࡢほⅬ࠿ࡽࡑࡢೃ⿵⸆ࡢ㛤Ⓨ᥎㐍࡟␲ၥࡀ ᣢࡓࢀࡿ࡜⪃࠼ࡽࢀࡿࠋᮏሗ࿌ࡢࢸ࣮࣐࡟㑅ᢥࡋࡓTAK-357 ࡢᢞ⸆࡟㉳ᅉࡋ࡞࠸ணᮇࡏࡠ⾑₢୰⃰ ᗘୖ᪼ࡣ㸪TAK-357 ࡢ㧗⬡⁐ᛶ࡜⬡⫫㔜㔞ኚ໬࡟㉳ᅉࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋࡼࡗ࡚㸪ࡇࡢ TAK-357 ࡢ࢖ࢾ࡟࠾ࡅࡿணᮇࡏࡠ⾑₢୰⃰ᗘୖ᪼ࡢཎᅉࢆ᥎ᐹࡋ㸪⬡⫫⤌⧊㔜㔞ኚ໬ࡀయෆືែ࡟

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୚࠼ࡿᙳ㡪ࢆホ౯ࡍࡿࡇ࡜ࡣ㸪TAK-357 ࡢ㛤Ⓨࢆ᥎㐍ࡋ࡚࠸ࡃୖ࡛࡟㠀ᖖ࡟㔜せ࡞◊✲࡛࠶ࡿ࡜⪃ ࠼ࡽࢀࡓࠋࡉࡽ࡟㸪TAK-357 ࢆ㧗⬡⁐ᛶ⸆≀ࡢ≉ᛶࢆ᭷ࡋࡓ௦⾲ⓗ⸆≀࡜఩⨨௜ࡅ㸪ࡑࡢ௚ࡢ㧗⬡ ⁐ᛶ⸆≀࡟࠾࠸࡚ࡶྠᵝࡢ⌧㇟ࡀ㉳ࡾ࠺ࡿ࠿᥎ᐹࡍࡿࡇ࡜ࡣ㸪୍⯡ⓗ࡞㧗⬡⁐ᛶ⸆≀ࡢయෆືែࢆண ࡍࡿୖ࡛㠀ᖖ࡟᭷⏝࡛࠶ࡿࠋ ࡑࡇ࡛ᮏㄽᩥ࡛ࡣୖグ┠ⓗࢆ㐩ᡂࡍࡿࡓࡵ࡟㸪௨ୗࡢ㡯┠࡟ࡘ࠸᳨࡚ウࡋࡓࠋ 1. ࢖ࢾ TK ヨ㦂᫬࡟ㄆࡵࡽࢀࡓணᮇࡏࡠ⾑₢୰⃰ᗘୖ᪼ࡢཎᅉࢆゎ᫂ࡋ㸪⸆≀ືែᏛⓗ᳨ドࢆ ⾜࠺ࡓࡵ࡟ࡣ㸪࢖ࢾࢆྵࡵࡓື≀࡟࠾ࡅࡿᇶᮏⓗ࡞ADME ≉ᛶࢆホ౯ࡋ㸪࡝ࡢ㐣⛬࡟ཎᅉࡀ࠶ࡿ࠿ ࢆ᥎ᐹࡍࡿࡇ࡜ࡀ᭷ຠ࡜⪃࠼ࡓࠋࡑࡇ࡛ᨺᑕ⬟ᶆ㆑ࡋࡓTAK-357 ([14_{C]TAK-357) ࢆࣛࢵࢺ࠾ࡼࡧ࢖} ࢾ࡟ᢞ୚ࡋࡓ㝿ࡢADME ≉ᛶࢆホ౯ࡋࡓࠋ 2. TAK-357 ࡢ㠀⮫ᗋ ADME ≉ᛶࡢホ౯࠿ࡽ㸪⬡⫫⤌⧊㔜㔞పୗ࡟ࡼࡾ⬡⫫⤌⧊୰࡟⵳✚ࡋࡓ TAK-357 ࡀ⾑₢୰࡟෌ศᕸࡍࡿࡇ࡜࡟ࡼࡗ࡚ணᮇࡏࡠ⾑₢୰⃰ᗘୖ᪼ࡀ㉳ࡁࡓ࡜ࡍࡿ௬ㄝࢆᥦ᱌ࡋ ࡓࠋࡑࡢ௬ㄝࡀᐃ㔞ⓗ࡟ㄝ࡛᫂ࡁࡿ࠿ྰ࠿ࢆ⏕⌮Ꮫⓗ⸆≀ືែ (PBPK) ࣔࢹࣝゎᯒ࡟ࡼࡾホ౯ࡋࡓࠋ 3. ⬡⫫⤌⧊㔜㔞ࡢᕪ␗ࡀ㧗⬡⁐ᛶ⸆≀ࡢయෆືែ࡟࡝ࡢࡼ࠺࡞ᙳ㡪ࢆ୚࠼ࡿ࠿ࢆTAK-357 ࢆࣔ ࢹࣝ⸆≀࡜ࡋ࡚ホ౯ࡋࡓࠋ⫧‶ື≀࡜ṇᖖື≀ࡢయෆືែࢆẚ㍑ࡋࡓୖ࡛㸪య⤌ᡂࡢ㐪࠸࡟ࡼࡿ㧗⬡ ⁐ᛶ⸆≀ࡢᢞ୚㔞ㄪᩚࡢᚲせᛶࢆPBPK ࣔࢹࣝゎᯒ࡟ࡼࡾᐃ㔞ⓗ࡟ホ౯ࡋࡓࠋ 㧗㧗⬡⁐ᛶ⸆≀ࡢ୍⯡ⓗ࡞⸆≀ືែᏛⓗ≉ᛶ 1.3 1.3.1 ⤌⧊ศᕸ࡟ࡘ࠸࡚ ⤌⧊ศᕸࡣ⸆≀ࡢయෆືែࢆ≉ᚩ௜ࡅࡿ㔜せ࡞せ⣲ࡢ୍ࡘ࡛࠶ࡿࠋ⤌⧊ศᕸࡀ୚࠼ࡿᙳ㡪ࡣ༢࡟ ⤌⧊୰ࡢ⸆≀⃰ᗘࡢࡳ࡛࡞ࡃ㸪⾑₢୰⃰ᗘࣞ࣋ࣝࡸ⾑₢୰༙ῶᮇ㸪⥲యෆ㈇Ⲵ㔞㸪᤼ἥ㏿ᗘ࡟ࡶ㛵ࢃ ࡿ (62)ࠋ⸆≀ࡢ⤌⧊ศᕸ࡟ࡣ⬡⁐ᛶ㸪Ⲵ㟁㸪ศᏊࢧ࢖ࢬ㸪ศᏊ❧యᵓ㐀㸪⸆≀⾲㠃✚➼ࡢ≀⌮໬Ꮫ ⓗᛶ㉁ࡢ௚㸪⾑₢⺮ⓑ⤖ྜ㸪⸆⌮ᶆⓗ➼ࡢ⺮ⓑ㉁࡬ࡢ≉␗ⓗ⤖ྜࡸࢺࣛࣥࢫ࣏࣮ࢱ࣮࡟ࡼࡿ㍺㏦࡞࡝ ࡀᐤ୚ࡍࡿ (20, 30, 51, 59, 66)ࠋ㧗⬡⁐ᛶ⸆≀ࡣ୍⯡ⓗ࡟⭷㏱㐣ᛶࡀࡼࡃ㸪⬡㉁ࢆྵࡴ⤌⧊࡬ከࡃ⛣⾜ ࡍࡿࡓࡵ㸪ศᕸᐜ✚ࡀ㧗ࡃ࡞ࡿഴྥ࡟࠶ࡿ (10, 16, 29)ࠋࡑࡢࡓࡵ㸪≉␗ⓗ࡞㍺㏦㸪⤖ྜ➼ࡀ㛵ࢃࡽ࡞

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࠸ሙྜ࡟ࡣࡑࡢ⤌⧊/⾑₢୰⃰ᗘẚࡣ࠾࠾ࡼࡑ⸆≀ࡢ⬡⁐ᛶ࡟౫Ꮡࡋ࡚࠸ࡿࡇ࡜ࡶሗ࿌ࡉࢀ࡚࠸ࡿ (22)ࠋ 1.3.2 ᾘኻ࡟ࡘ࠸࡚ ⸆≀ࡢ୺ࡓࡿᾘኻ⤒㊰ࡣᮍኚ໬య࡜ࡋ࡚ࡢᒀ୰᤼ἥ㸪⫹Ồ᤼ἥ࠾ࡼࡧ௦ㅰ࡛࠶ࡿࠋᒀ୰᤼ἥࡣ୺ ࡟⬡⁐ᛶࡢప࠸⸆≀ࡀ᤼ἥࡉࢀࡿࡓࡵ㸪㧗⬡⁐ᛶ⸆≀ࡀᮍኚ໬య࡜ࡋ࡚ᒀ୰࡟᤼ἥࡉࢀࡿྍ⬟ᛶࡣ㠀 ᖖ࡟ప࠸ (21)ࠋ⸆≀௦ㅰࡣ୺࡟⫢⮚ࡸᑠ⭠࡛㉳ࡇࡿ␗≀㝖ཤࢩࢫࢸ࣒࡛࠶ࡾ㸪ᴫࡋ࡚⸆≀ࡢ⬡⁐ᛶ ࢆୗࡆࡿࡇ࡜࡟ࡼࡾ᤼ἥࡉࢀࡸࡍࡃࡍࡿ (68)ࠋࡑࡢࡓࡵከࡃࡢ㧗⬡⁐ᛶ⸆≀ࡣ௦ㅰࢆཷࡅࡓᚋ࡟௦ ㅰ≀࡜ࡋ࡚ᒀ୰ཪࡣ⫹Ồࢆ௓ࡋ࡚⣅୰࡟᤼ἥࡉࢀࡿ (5, 9, 53)ࠋࡲࡓ㸪௦ㅰ⤌⧊࡛࠶ࡿ⫢⮚࡬ࡢ⛣⾜࡟

ࡣࢺࣛࣥࢫ࣏࣮ࢱ࣮࡛࠶ࡿOrganic anion transprter polypeptide (OATP) ࡀ㛵୚ࡍࡿሙྜࡶ࠶ࡿ (5, 43)ࠋ ⸆≀ࡢ⁐ゎᗘཬࡧ௦ㅰ㏿ᗘ࠿ࡽࡑࡢືែ≉ᛶࢆ᥎ᐃࡍࡿBiopharmaceutics Drug Disposition

Classification System (BDDCS) ࡟ࡼࡿศ㢮࡟࠾࠸࡚㸪⁐ゎᗘࡢప࠸㧗⬡⁐ᛶ⸆≀ࡣࢡࣛࢫ 2 ࡲࡓࡣࢡ ࣛࢫ4 ࡟ศ㢮ࡉࢀࡿ (8)ࠋ௦ㅰ㏿ᗘࡀ㏿࠸ࢡࣛࢫ 2 ࡢ⸆≀ࡣ⭠⟶࡟࠾ࡅࡿ᤼ฟࢺࣛࣥࢫ࣏࣮ࢱ࣮࠾ࡼ ࡧ⫢⮚࡟࠾ࡅࡿྲྀࡾࡇࡳཬࡧ᤼ฟࢺࣛࣥࢫ࣏࣮ࢱ࣮ࡢᙳ㡪ࢆཷࡅࡸࡍ࠸ࠋ୍᪉࡛௦ㅰ㏿ᗘࡢ㐜࠸ࢡࣛ ࢫ4 ࡛ࡣ྾཰࠾ࡼࡧ᤼ἥࢺࣛࣥࢫ࣏࣮ࢱ࣮ࡢᙳ㡪ࢆཷࡅࡿྍ⬟ᛶࡣ࠶ࡿࡶࡢࡢ㸪౛ᩘࡀᑡ࡞࠸ࡓࡵࡑ ࡢഴྥࡣ᫂☜࡛ࡣ࡞࠸ࠋ 1.3.3 ⤒ཱྀ྾཰࡟ࡘ࠸࡚ ⸆≀ࡢ⤒ཱྀ྾཰ᛶ࡟ࡣ〇๣࠿ࡽࡢ⁐ฟ㸪⸆≀ࡢ⁐ゎᛶ㸪⭷㏱㐣ᛶ࡞࡝ࡀ㛵ಀࡍࡿࠋ⏕⌮Ꮫⓗせᅉ ࡜ࡋ࡚ࡣ⫶ෆࡸ⭠⟶ෆࡢpH㸪ᾘ໬⟶ෆᐜ≀ࡢ᭷↓㸪⭠⟶㐠ື࡞࡝ࡀ྾཰࡟ᙳ㡪ࢆ୚࠼ࡿ (52)ࠋ⁐ゎ ᗘࡀ㧗ࡃ㸪⭷㏱㐣ᛶࡢ㧗࠸⸆≀ࡀ྾཰ࡉࢀࡸࡍ࠸⸆≀࡛࠶ࡿ (7)ࠋ㧗⬡⁐⸆≀ࡣ୍⯡ⓗ࡟⭷㏱㐣ᛶࡣ 㧗࠸ࡀ⁐ゎᗘࡀప࠸ࡓࡵ㸪⏝㔞ࡀୖ᪼ࡍࡿ࡟ᚑ࠸⁐ゎ࡛ࡁࡿ⸆≀ࡢᢞ୚㔞࡟ᑐࡍࡿẚ⋡ࡀపୗࡋ㸪ࡑ ࡢ⤖ᯝ྾཰⋡ࡣపୗࡍࡿࠋࡲࡓ㸪⁐ゎᗘࡀప࠸ࡓࡵ㸪ࡑࡢ⁐ゎᛶ࡟ᙳ㡪ࢆ୚࠼ࡿ⫶ෆpH ࡸᦤ㣵ࡢ᭷ ↓➼࡟ᙳ㡪ࢆཷࡅࡸࡍ࠸ࡀ㸪ᦤ㣵ᕪࡢண ࡣ㠀ᖖ࡟㞴ࡋ࠸ࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿ (60)ࠋ

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TAK-357 ࡟࡟ࡘ࠸࡚ 1.4

1.4.1 ≀⌮໬Ꮫⓗᛶ㉁

TAK-357 (1-(4-methoxyphenyl)-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran- 5-yl)piperazine㸪 Fig. 1-1) ࡣ࢔ࣝࢶࣁ࢖࣐࣮⑓ࡢ἞⒪⸆ࢆ┠ᣦࡋ࡚㛤Ⓨࡉࢀ࡚ࡁࡓ⸆≀࡛࠶ࡿࠋTAK-357 ࡣ logD: 5.83

࡜㠀ᖖ࡟⬡⁐ᛶࡢ㧗࠸⸆≀࡛࠶ࡾ㸪⏕⌮ᏛⓗpH࡟࠾࠸࡚ከࡃࡀ㠀ゎ㞳ᆺ࡜ࡋ࡚Ꮡᅾࡍࡿ⸆≀࡛࠶ࡿࠋ 㓟ゎ㞳ᣦᩘ (pKa) ࡣ 6.6,࠾ࡼࡧ 3.7 ࡛࠶ࡾ㸪ศᏊ㔞ࡣ 380.5 ࡛࠶ࡿࠋᮏ◊✲࡛ࡣ TAK-357 ཪࡣᨺᑕ⬟ ࡛ᶆ㆑ࡋࡓTAK-357 ([14_{C]TAK-357) ࢆ⏝࠸࡚⸆≀ືែホ౯ࢆ⾜ࡗࡓࠋ} 1.4.2 ᢠ࢔ࣝࢶࣁ࢖࣐࣮⑓⸆ࡢ⌧≧࡜ TAK-357 ࡢ⸆⌮స⏝ ࢔ࣝࢶࣁ࢖࣐࣮⑓ࡣ⮫ᗋデ᩿࡜ࡋ࡚࢚ࣆࢯ࣮ࢻグ᠈㞀ᐖࡢ㐍⾜࠿ࡽጞࡲࡾ㸪඲యⓗ࡞ㄆ▱⬟ຊࡢ పୗࡲ࡛⦆ࡸ࠿࡟㐍⾜ࡋ㸪᭱⤊ⓗ࡟Ṛ࡟⮳ࡿ⑌ᝈ࡛࠶ࡿ (19)ࠋ࢔ࣝࢶࣁ࢖࣐࣮⑓ᝈ⪅ᩘࡣୡ⏺࡛ 2015 ᖺ⌧ᅾ4680 ୓ே࡟㐩ࡋ㸪2050 ᖺ࡟ࡣ 1 ൨ 3200 ୓࡟ቑຍࡍࡿ࡜⪃࠼ࡽࢀ࡚࠸ࡿ (6)ࠋ࢔ࣝࢶࣁ࢖࣐࣮ ⑓ࡢཎᅉ࡜ࡋ࡚ࡣ㸪࢔࣑ࣟ࢖ࢻ 42 (A 42) ࡢจ㞟࠾ࡼࡧ⵳✚࡟ጞࡲࡾ㸪ࢱ࢘ࡢࣜࣥ㓟໬ࢆ௓ࡋࡓ⚄ ⤒ኚᛶࡸ⚄⤒⣽⬊Ṛ㸪ࡲࡓࡣࢱ࢘ࡢࣜࣥ㓟໬ࢆ௓ࡉ࡞࠸⤒㊰࡟ࡼࡿࢩࢼࣉࢫ㺃⚄⤒⣽⬊ࡢᶵ⬟㞀ᐖ࡞ ࡝࡟ࡼࡿㄆ▱⬟ຊࡢపୗࡀ♧၀ࡉࢀ࡚࠸ࡿ (69)ࠋ⌧ᅾ㸪࢔ࢭࢳࣝࢥ࢚ࣜࣥࢫࢸ࣮ࣛࢮ㜼ᐖ⸆ࡸ N-methyl-d-aspartate (NMDA) ཷᐜయᣕᢠ⸆࡞࡝ࡀ࢔ࣝࢶࣁ࢖࣐࣮ᝈ⪅ࡢㄆ▱ᶵ⬟ࡢᨵၿࡢࡓࡵ࡟ฎ ᪉ࡉࢀ࡚࠸ࡿ (25, 31, 44)ࠋࡋ࠿ࡋ࡞ࡀࡽ㸪࢔ࣝࢶࣁ࢖࣐࣮⑓ࡣ౫↛࡜ࡋ࡚⚄⤒⑌ᝈ㡿ᇦࡢ୰࡛ࡶ㧗࠸ ࢔࣓ࣥࢵࢺ࣓ࢹ࢕࢝ࣝࢽ࣮ࢬࡀ࠶ࡾ㸪Ṛᅉ࡜ࡋ࡚ࡢ๭ྜࡀୖ᪼ࡋ࡚࠸ࡿ (61)ࠋࡑࡢࡓࡵ㸪᪂ࡓ࡞἞ ⒪࢜ࣉࢩࣙࣥࡢ㛤Ⓨࡀᚲせ࡛࠶ࡾ㸪௒ᚋࡢ◊✲ࡢ㐍ᒎࡀᮃࡲࢀ࡚࠸ࡿࠋ⌧ᅾ㸪ୖ㏙ࡢ἞⒪࣓࢝ࢽࢬ࣒ ࢆ᭷ࡋࡓ⸆≀ࡢ௚࡟㸪 ࢭࢡࣞࢱ࣮ࢮ㜼ᐖ⸆㸪 ࢭࢡࣞࢱ࣮ࢮ㜼ᐖ⸆㺃ㄪ⠇⸆㸪A ࣡ࢡࢳࣥ࡞࡝ࡢ㛤 Ⓨࡀ㐍ࡵࡽࢀ࡚࠸ࡿ (17, 33, 45)ࠋTAK-357 ࡣᾏ㤿࠾ࡼࡧ኱⬻⓶㉁⏤᮶ࡢึ௦ᇵ㣴⚄⤒⣽⬊࡟࠾࠸࡚㸪 ࢖ࣥࢫࣜࣥᵝቑṪᅉᏊ1 (IGF1) ࡜༠ാࡍࡿࡇ࡜࡟ࡼࡾ⚄⤒ಖㆤస⏝ࢆ♧ࡋ㸪࢔ࣝࢶࣁ࢖࣐࣮⑓ࡢ἞ ⒪⸆ࢆ┠ᣦࡋ࡚㛤Ⓨࡉࢀ࡚ࡁࡓ (63),ࠋ

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TAK-357 ࡢࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾ࡅࡿయෆືែ

➨

2❶

ࡣࡌࡵ࡟ 2.1 ⸆≀ືែホ౯ࡣ㛤Ⓨ⸆≀ࡢ㠀⮫ᗋ࠾ࡼࡧ⮫ᗋヨ㦂࡟࠾ࡅࡿ⸆ຠ࠾ࡼࡧᏳ඲ᛶࢆ⥲ྜⓗ࡟ホ౯ࡍࡿ ࡟ᙜࡓࡾᚲ㡲ࡢ㡯┠࡛࠶ࡿ (57)ࠋTAK-357 ࡣ᥈⣴ⓗ⸆≀ືែホ౯࡟ࡼࡾ㠀ᖖ࡟㛗࠸⾑₢୰༙ῶᮇࡀ ♧ࡉࢀ࡚࠸ࡿࠋ୍⯡ⓗ࡟㛤Ⓨ⸆≀ࡢయෆ࠿ࡽࡢ᤼ἥࡀ୙᏶඲࡛࠶ࡿሙྜࡸ⾑₢୰༙ῶᮇࡀ㠀ᖖ࡟㛗࠸ ሙྜ࡟ࡣ㸪ࡑࡢ࣓࢝ࢽࢬ࣒᥎ᐃࡀᚲ㡲࡜࡞ࡿࠋࡑࡢ⌮⏤ࡣ㸪ձࡶࡋ㛤Ⓨ⸆≀ཪࡣࡑࡢ௦ㅰ≀ࡀ࠶ࡿ⤌ ⧊⺮ⓑ࡬ඹ᭷⤖ྜ➼ࡢ≉␗ⓗ࡞⤖ྜࢆࡍࡿሙྜ࡟ࡣ㸪⮫ᗋ࠾ࡼࡧ㠀⮫ᗋ࡟࠾࠸࡚Ᏻ඲ᛶࡢᠱᛕࡶ⪃࠼ ࡽࢀࡿ㸪ղ཯᚟ᢞ୚ᚋ࡟ᐃᖖ≧ែ࡟㐩ࡍࡿࡲ࡛ࡢ᫬㛫ࡀ㛗ࡃ㸪ࡑࡢ⃰ᗘࡢ᥎ᐃࡀ㞴ࡋࡃ࡞ࡿ㸪ճᏳ඲ ᛶୖࡢၥ㢟ࡀⓎ⏕ࡋࡓ㝿࡟ࡣ㸪⸆≀ࡢయෆ࠿ࡽࡢ㝖ཤࡶ㞴ࡋࡃ࡞ࡿ࡞࡝ࡀ࠶ࡿࠋࡲࡓ㸪௒ᅇ࢖ࢾࢆ⏝ ࠸ࡓTK ヨ㦂࡛ㄆࡵࡽࢀࡓ⾑₢୰⃰ᗘୖ᪼ࡢཎᅉࢆ᥎ᐹࡍࡿୖ࡛ࡶTAK-357 ࡢADME ࢆᢕᥱࡍࡿࡇ ࡜ࡣᴟࡵ࡚㔜せ࡛࠶ࡿࠋࡑࡇ࡛ᮏ❶࡛ࡣ[14_{C]TAK-357 ཪࡣ TAK-357 ࢆ⏝࠸ࡓࣛࢵࢺ㸪࢖ࢾ࡟࠾ࡅࡿ} యෆືែヨ㦂ࢆᐇ᪋ࡋ㸪㛗࠸⾑₢୰༙ῶᮇࡸ࢖ࢾ࡛ㄆࡵࢀࢀࡓ⾑₢୰⃰ᗘୖ᪼ࡢཎᅉࢆᐃᛶⓗ࡟᥎ᐹ ࡋࡓࠋ ᐇ㦂ᮦᩱ࡜᪉ἲ 2.2 2.2.1 ⿕㦂≀㉁㸪ヨ⸆ TAK-357 ࡣṊ⏣⸆ရᕤᴗᰴᘧ఍♫㸪〇⸆◊✲ᡤ࡛ྜᡂࡉࢀࡓࡶࡢࢆ⏝࠸ࡓࠋ[14_{C]TAK-357 (ᨺᑕ⛉} Ꮫⓗ⣧ᗘ>97%㸪㠀άᛶ:5.75 MBq/mg) ࡣࣅ࢜ࣈࣜࢵࢪᰴᘧ఍♫ (ᮾி) ࡛ྜᡂࡉࢀࡓࡶࡢࢆ⏝࠸ࡓࠋ ࡑࡢ௚ࡢヨ⸆࡜ヨᾮࡣศᯒࢢ࣮ࣞࢻࡢࡶࡢࢆ㉎ධࡋࡓࠋ 2.2.2 ື≀ 㞝ᛶCrj:CD(SD)ࣛࢵࢺ (᪥ᮏࢳ࣮ࣕࣝࢫࣜࣂ࣮㸪⚄ዉᕝ) ࠾ࡼࡧ㞝ᛶࣅ࣮ࢢࣝ≟ (໭ᒣࣛ࣋ࢫ㸪ᒣ ཱྀ) ࢆ⏝࠸ࡓࠋࣛࢵࢺࡣ㞝ᛶࡢᢞ୚᫬8 㐌㱋ࡢື≀ࢆn=3 ཪࡣn=4 ࡛⏝࠸ࡓࠋ㣗㣵ࡣᅛᙧ㣫ᩱ CR-LPF (࢚࢜ࣜࣥࢱࣝ㓝ẕ㸪ᮾி) ࢆ⮬⏤ᦤ㣵࡜ࡋ㸪Ỉࡣ⮬⏤㣧Ỉ࡜ࡋࡓࠋ㣫⫱ࡣࢫࢸࣥࣞࢫࢣ࣮ࢪ࡛⾜࠸㸪

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ᦙධᚋ1 㐌㛫௨ୖࡢ㥆໬ࡢᚋ㸪ヨ㦂࡟౑⏝ࡋࡓࠋ࢖ࢾࡣᢞ୚᫬ 7-24 㐌㱋࡛య㔜 9.8-12.0 kg ࡢ㞝ᛶࡢ ࣅ࣮ࢢࣝ≟ࢆn=3 ཪࡣ n=4 ࡛⏝࠸ࡓࠋࢫࢸࣥࣞࢫࢣ࣮ࢪෆ࡛㣫⫱ࡋ㸪ᅛᙧ㣫ᩱ Labo D stock (᪥ᮏ㎰ ⏘ ⚄ዉᕝ) ࢆ 1 ᪥ 1 ᅇ 250 g ⤥㣵ࡋ㸪Ỉࡣ⮬⏤ᘬỈ࡜ࡋࡓࠋ 2.2.3 ⿕㦂≀㉁ࡢᢞ୚࠾ࡼࡧ⏕యヨᩱࡢ᥇ྲྀ ⤒ཱྀᢞ୚ࡢሙྜࡣ[14C]TAK-357 ࡲࡓࡣ TAK-357 ࢆ 0.5% (w/v) ࣓ࢳࣝࢭ࣮ࣝࣟࢫ (ಙ㉺໬Ꮫ㸪ᮾி) ⁐ᾮ࡟ᠱ⃮ࡋࡓࠋ[14_{C]TAK-357 ࡣ 3 mg/kg ࡢ⏝㔞࡛ࣛࢵࢺ (⾑₢୰ PK ヨ㦂࡛ࡣ 17.3 MBq/kg㸪᤼ἥ} ヨ㦂࡛ࡣ2.3 MBq/kg㸪⤌⧊ศᕸヨ㦂࡛ࡣ 8.7 MBq/kg) ࠾ࡼࡧ࢖ࢾ (4.3 MBq/kg) ࡟⤒ཱྀᢞ୚ࡋࡓࠋ TAK-357 ࡣ 0.3, 1 ࠾ࡼࡧ 3 mg/kg ࡢ⏝㔞࡛ࣛࢵࢺ࡟㸪3 mg/kg ࡢ⏝㔞࡛࢖ࢾ࡟⤒ཱྀᢞ୚ࡋࡓࠋ㟼⬦ෆ ᢞ୚ࡢሙྜࡣTAK-357 ࢆࢪ࣓ࢳࣝ࢔ࢭࢺ࢔࣑ࢻ (࿴ග⣧⸆ᕤᴗ㸪኱㜰)࠾ࡼࡧ1,3-ࣈࢱࣥࢪ࣮࢜ࣝ (࿴ ග⣧⸆ᕤᴗ) ࡢΰྜᾮ (1:1, v/v) ࡟⁐ゎࡋ㸪1 mg/kg ࡢ⏝㔞࡛ࣛࢵࢺ (n=3) ࠾ࡼࡧ࢖ࢾ (n=4) ࡟ᢞ୚ ࡋࡓࠋᢞ୚ࡣ㣬㣗ୗ࡟⾜ࡗࡓࠋ [14_{C]TAK-357 ཪࡣ TAK-357 ᢞ୚ᚋ࡟ࣛࢵࢺࡢᑿ㟼⬦ࡲࡓࡣ࢖ࢾࡢᶨഃ⓶㟼⬦࠿ࡽタᐃࡋࡓ᫬㛫࡟} ᥇⾑ࡋࡓࠋᢠจᅛ๣࡟ࡣ࣊ࣃࣜࣥࢼࢺ࣒ࣜ࢘ࢆ⏝࠸㸪⾑ᾮヨᩱࡣ4°C ࡛ 10,000×g ࡛ 3 ศ㛫㐲ᚰࡍࡿ ࡇ࡜࡟ࡼࡾ⾑₢ヨᩱࢆㄪ〇ࡋࡓࠋ⤌⧊ศᕸヨ㦂࡛ࡣ㸪[14_{C]TAK-357 ࢆ⤒ཱྀᢞ୚ 0.5㸪2㸪8㸪24㸪168㸪} 332 ࠾ࡼࡧ 672 ᫬㛫ᚋ࡟ࣛࢵࢺࢆ࢖ࢯࣇࣝࣛࣥ㯞㓉ୗ࡛ᨺ⾑⮴Ṛࡉࡏࡓࠋࡑࡢᚋ㸪⬻㸪⬨㧊㸪ୗᆶయ㸪 ║⌫㸪ࣁ࣮ࢲ࣮⭢㸪㢡ୗ⭢㸪⏥≧⭢㸪⬚⭢㸪ᚰ⮚㸪⫵㸪⫢⮚㸪⭁⮚㸪⮅⮚㸪๪⭈㸪⭈⮚㸪⢭ᕢ㸪㦵᱁ ➽㸪⓶⭵㸪⭈࿘ᅖ⬡⫫㸪⢭ᕢ࿘ᅖ⬡⫫㸪〓Ⰽ⬡⫫㸪㦵㧊㸪⫶㸪⭠࠾ࡼࡧ኱⭣㦵ࢆ᥇ྲྀࡋࡓࠋࡲࡓ㸪࢖ ࢾ࡟࠾࠸࡚ࡣ[14_{C]TAK-357 ࢆ⤒ཱྀᢞ୚ᚋࡢ 672 ᫬㛫࡟࣌ࣥࢺࣂࣝࣅࢱ࣮ࣝࢼࢺ࣒ࣜ࢘㯞㓉ୗ࡛ᨺ⾑} ⮴Ṛࡉࡏ㸪⬻㸪⫵㸪⫢⮚㸪⭈⮚㸪⭈࿘ᅖ⬡⫫࠾ࡼࡧ⢭ᕢ࿘ᅖ⬡⫫ࢆ᥇ྲྀࡋࡓࠋ ࣛࢵࢺࡢᒀ࠾ࡼࡧ⣅ࡣ௦ㅰࢣ࣮ࢪෆ࡛ศ㞳ࡋ࡚᥇ྲྀࡋ㸪ᢞ୚ᚋ24 ᫬㛫ࡲ࡛ࡣ࿧Ẽ୰࡟ྵࡲࢀࡿ஧ 㓟໬Ⅳ⣲ࡶ᥇ྲྀࡋࡓࠋ࢖ࢾࡢ᤼ἥ≀ࡣᢞ୚ᚋ168 ᫬㛫ࡲ࡛௦ㅰࢣ࣮ࢪෆ࡛᥇ྲྀࡋ㸪ࡑࡢᚋࡣ㣫⫱ࢣ࣮ ࢪ࡛㣫⫱ࡋࡓࠋ඲࡚ࡢື≀ヨ㦂ࡣᰴᘧ఍♫ࢿࣔࢺ࣭ࢧ࢖࢚ࣥࢫ (Ⲉᇛ) ࡟࡚ᐇ᪋ࡉࢀࡓࠋࡇࢀࡽࡢヨ㦂ࡣᰴᘧ఍♫ࢿࣔࢺ࣭ࢧ࢖࢚ࣥࢫື≀ᐇ㦂೔⌮ጤဨ఍࡟࡚ホ౯㸪ᢎㄆࡉࢀࡓࠋ

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2.2.4 ⾑₢⺮ⓑ⤖ྜ࠾ࡼࡧ⾑⌫⛣⾜

࣐࢘ࢫ࠾ࡼࡧࣛࢵࢺࡢࢥࣥࢺ࣮ࣟࣝ⾑₢࠾ࡼࡧ⾑ᾮࡣ᪥ᮏࢳ࣮ࣕࣝࢫࣜࣂ࣮ࡼࡾ㉎ධࡋࡓࠋ࢖ࢾ

ࡢࢥࣥࢺ࣮ࣟࣝ⾑₢࠾ࡼࡧ⾑ᾮࡣᰴᘧ఍♫ࢼࣝࢡ (༓ⴥ) ࡼࡾ㉎ධࡋࡓࠋࣄࢺࡢࢥࣥࢺ࣮ࣟࣝ⾑₢ࡣ

Interstate Blood Bank (ࢸࢿࢩ࣮) ࡼࡾ㉎ධࡋࡓࠋࣄࢺࡢࢥࣥࢺ࣮ࣟࣝ⾑ᾮࡣ⑓㝔࡟࡚᥇ྲྀࡋࡓࠋࢥࣥࢺ

࣮ࣟࣝ⾑ᾮ࠾ࡼࡧ⾑₢ࡣࡑࢀࡒࢀ5 ࠾ࡼࡧ 10 ேࡢ೺ᖖே࣎ࣛࣥࢸ࢕࢔ࡼࡾ᥇ྲྀࡉࢀ㸪ΰ࿴ࡉࢀࡓࡶ

ࡢࢆ⏝࠸ࡓࠋࣄࢺ⾑Ύ࢔ࣝࣈ࣑ࣥ (HSA) ࠾ࡼࡧࣄࢺ 1㓟ᛶ⢾⺮ⓑ (AGP) ࡣ Sigma-Aldrich japan (ᮾ ி) ࡼࡾ㉎ධࡋࡓࠋ

⺮ⓑ⤖ྜࡢホ౯ࡢࡓࡵ࡟㸪࣐࢘ࢫ㸪ࣛࢵࢺ㸪࢖ࢾ࠾ࡼࡧࣄࢺࡢ⾑₢㸪4% HSA, 0.05% AGP ࠾ࡼࡧ

0.05% AGP ࡜ 4% HSA ࡢΰᾮ࡟[14_{C]TAK-357 ࢆῧຍࡋࡓ (⤊⃰ᗘ: 0.1, 1, 10 g/mL, n=3)ࠋࡇࡢ⾑₢ࢆ} 274,000 ཪࡣ 316,000×g㸪4°C ࡛ 14 ᫬㛫㉸㐲ᚰࡋࡓࠋ㉸㐲ᚰୖΎ୰࠾ࡼࡧ⾑₢୰ࡢᨺᑕ⬟ࡣୗグ࡟グ㍕ࡢ᪉ἲ࡛ ᐃࡋࡓࠋ⺮ⓑ⤖ྜ⋡ࡣᘧ2-1 ࢆ⏝࠸࡚⟬ฟࡋࡓࠋ ⺮ⓑ⤖ྜ⋡ (%) = × ᘧ2-1 CPL:⾑₢୰ᨺᑕ⬟⃰ᗘ Csup: ㉸㐲ᚰୖΎ୰ᨺᑕ⬟⃰ᗘ ⾑⌫⛣⾜⋡ࡢホ౯ࡢࡓࡵ࡟ࡣࣛࢵࢺ㸪࢖ࢾ࠾ࡼࡧࣄࢺࡢ⾑ᾮ࡟[14_{C]TAK-357 ࢆῧຍࡋࡓ (⤊⃰ᗘ:} 0.1, 1, 10 g/mL, n=3)ࠋ37°C ࡛ 30 ศ㛫࢖࣮ࣥ࢟ࣗ࣋ࢺࡋࡓᚋ࡟⾑ᾮ୰࠾ࡼࡧ⾑₢୰ࡢᨺᑕ⬟⃰ᗘࢆ ᐃࡋ㸪࣐࣊ࢺࢡࣜࢵࢺ್(Hct)ࡶ ᐃࡋࡓࠋ⾑⌫⛣⾜⋡ࡣᘧ 2-2 ࢆ⏝࠸࡚⟬ฟࡋࡓࠋ ⾑⌫⛣⾜⋡ (%) = 100 ×( ) ᘧ2-2 CWB:⾑ᾮ୰ᨺᑕ⬟⃰ᗘ 2.2.5 ᨺᑕ⬟ࡢ ᐃ ⏕యヨᩱ࠾ࡼࡧ᭷ᶵ⁐፹ᢳฟᾮ୰ࡢᨺᑕ⬟ࡣᾮయࢩࣥࢳ࣮ࣞࢩࣙࣥ࢝࢘ࣥࢱ࣮(LSC㸪᪥❧࢔ࣟ࢝ ࣓ࢹ࢕࢝ࣝ㸪ᮾி)ࢆ⏝࠸࡚ ᐃࡋࡓࠋ⥲ᨺᑕ⬟⃰ᗘࡣ ᐃᨺᑕ⬟್࡜ẚάᛶ࠿ࡽ⟬ฟࡋࡓࠋࡲࡓ㸪

(17)

௦ㅰ≀ࡢ⃰ᗘࡣ⥲ᨺᑕ⬟୰ࡢᣨศẚࢆ஌ࡍࡿࡇ࡜࡟ࡼࡾ⟬ฟࡓࠋ⥲ᨺᑕ⬟࠾ࡼࡧ௦ㅰ≀⃰ᗘࡣศᏊ㔞 ࢆTAK-357 ࡜ྠࡌ࡜ࡋࡓ TAK-357 ᥮⟬್࡜ࡋ࡚⾲グࡋࡓࠋ⾑₢㸪ᒀ㸪⣅࣍ࣔࢪࢿ࣮ࢺ୰ࡢ⤌ᡂศᯒ ࡟ࡣᨺᑕᛶྠ఩ඖ⣲᳨ฟჾ (625TR㸪ࣃ࣮࢚࣐࣮࢟ࣥࣝࢪࣕࣃࣥ㸪⚄ዉᕝ) ࢆ᥋⥆ࡋࡓ㧗㏿ᾮయࢡࣟ ࣐ࢺࢢࣛࣇ࢕࣮(HPLC㸪ᓥὠ〇సᡤ㸪ி㒔)ࢆ⏝࠸ࡓࠋ⬡⫫⤌⧊୰ࡢ⤌ᡂศᯒ࡟ࡣ HPLC ࡛ศ㞳ᚋ㸪 ࣇࣛࢡࢩࣙࣥࢥࣞࢡࢺἲ࡛⁐ฟᾮࢆ᥇ྲྀᚋ㸪LSC ࢆ⏝࠸࡚ᨺᑕ⬟ࢆ ᐃࡋࡓࠋ⤌ᡂศᯒࡢࡓࡵ࡟⾑ ₢ヨᩱࡣ᥇ྲྀ᫬Ⅼࡈ࡜࡟ΰ࿴ࡋࡓࠋ⾑₢࠾ࡼࡧ⣅࣍ࣔࢪࢿ࣮ࢺヨᩱ୰ࡢTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀ ㉁ࡣ࢔ࢭࢺࢽࢺ࡛ࣜࣝᢳฟࡋ㸪⬡⫫⤌⧊ヨᩱ࡛ࡣࢡ࣒ࣟࣟ࣍ࣝ/࣓ࢱࣀ࣮ࣝΰᾮ (2:1㸪v/v)࡛ ᢳฟࡋ ࡓࠋᒀࡣ㐲ᚰୖΎࢆHPLC ศᯒヨᩱ࡜ࡋࡓࠋ๓ฎ⌮ࡋࡓヨᩱࡣ 40°C ࡟タᐃࡋࡓ L-column ODS (5 μm, 250 mm × 4.6 mm i.d., ໬Ꮫ≀㉁ホ౯◊✲ᶵᵓ㸪ᮾி) ࢆタ⨨ࡋࡓ HPLC ࡟ὀධࡋࡓࠋ⛣ື┦ A ࡟ࡣ 10 mmol/L 㓑㓟࢔ࣥࣔࢽ࣒࢘/࢔ࢭࢺࢽࢺࣜࣝΰᾮ (9:1, v/v) ࢆ㸪⛣ື┦ B ࡟ࡣ 10 mmol/L 㓑㓟࢔ࣥࣔ ࢽ࣒࢘/࢔ࢭࢺࢽࢺࣜࣝΰᾮ (1:9, v/v) ࢆ⏝࠸㸪ὶ㔞ࢆ 1 mL/min ࡜ࡋࡓࠋࢢࣛࢪ࢚ࣥࢺࣉࣟࢢ࣒ࣛ࡜ ࡋ࡚50%⛣ື┦ B ࠿ࡽ㛤ጞࡋ㸪10 ศࡲ࡛࡟ 100%⛣ື┦ B ࡟┤⥺ⓗ࡟ୖ᪼ࡉࡏࡓࠋ15 ศ㛫 100%⛣ ື┦B ࢆ⥔ᣢᚋ࡟ 50%⛣ື┦ B ࡟ 0.1 ศ㛫࡛ᡠࡋ㸪10.9 ศ㛫࠿ࡅ࡚෌ᖹ⾮໬ࡋࡓࠋ1 ὀධẖࡢ⥲ࢧ࢖ ࢡࣝ᫬㛫ࡣ36 ศ࡛࠶ࡿࠋ᭷ᶵ⁐፹࡟ࡼࡿ㠀ᢳฟᡂศ࠾ࡼࡧᐃ㔞ୗ㝈ᮍ‶ࡢศ⏬ࡣᮍྠᐃ௦ㅰ≀࡜ࡋ ࡚⟬ฟࡋࡓࠋ 2.2.6 ⾑₢୰ TAK-357 ࡢᐃ㔞⾑₢ヨᩱ୰ࡢTAK-357 ࡣ㉁㔞ศᯒჾࢆ᥋⥆ࡋࡓHPLC (LC/MS/MS) ࢆ⏝࠸࡚ᐃ㔞ୗ㝈1 ng/m ࡛ᐃ 㔞ࡋࡓࠋ⾑₢ヨᩱࡣ࣓ࢱࣀ࣮࡛ࣝ㝖⺮ⓑࡋ㸪㐲ᚰୖΎࢆ⛣ື┦࡛ᕼ㔘ࡋࡓᚋ࡟40°C ࡟タᐃࡋࡓ

AC UITY UPLC BEH C18 (1.7 m, 2.1 × 50 mm, Waters㸪࣐ࢧࢳ࣮ࣗࢭࢵࢶ) ࢆ᥋⥆ࡋࡓ LC/MS/MS (API4000, Applied Biosystems/MDS SCIEX, ࢝ࣝࣇ࢛ࣝࢽ࢔) ࡟ὀධࡋࡓࠋ࣓ࢱࣀ࣮ࣝ/Ỉ/ࢠ㓟 =700:300:2, v/v ࠿ࡽ࡞ࡿᆒ୍⃰ᗘࡢ⛣ື┦࡛ 2.5 ศ㛫࠿ࡅ࡚㸪ὶ㏿ 0.5 mL/min ࡛ࢡ࣐ࣟࢺࢢࣛࣇศ㞳 ࢆ⾜ࡗࡓࠋTAK-357 ࡣ m/z 381 191 ࡢ multiple reaction monitoring (MRM) ࣮ࣔࢻ᳨࡛ฟࡋ㸪ෆᶆ‽࡜

(18)

ࡋ࡚㛵㐃≀㉁ (m/z 433 134) ࢆ⏝࠸ࡓࠋศᯒἲࡣࣂࣜࢹ࣮ࢺࡉࢀ࡚࠾ࡾ㸪᳨㔞⥺⠊ᅖ 1-1000 ng/mL

࡛࠶ࡗࡓࠋ⢭ᗘ࠾ࡼࡧ┿ᗘࡣࡑࢀࡒࢀ0.7%-6.7%࠾ࡼࡧ-2.1%-6.7%࡛࠶ࡗࡓࠋ

2.2.7 ࢹ࣮ࢱฎ⌮

⤊ᮎ┦ࡢ⾑₢୰༙ῶᮇ (t1/2)㸪⸆≀⃰ᗘ᫬㛫᭤⥺ୗ㠃✚ (AUC)㸪඲㌟ࢡࣜ࢔ࣛࣥࢫ (CLp)㸪ᐃᖖ≧

ែ࡟࠾ࡅࡿศᕸᐜ✚ (Vss) ࡣWinNonlinࢯࣇࢺࣇ࢙࢔ (ࣂ࣮ࢪࣙࣥ6.1㸪Certara㸪ࢽ࣮ࣗࢪ࣮ࣕࢪ࣮) ࢆ ⏝࠸ࡓnon-conpartment ゎᯒἲ࡟ࡼࡾィ⟬ࡋࡓࠋ᭱኱⾑₢୰⃰ᗘ (Cmax) ࠾ࡼࡧ Cmax࡟฿㐩ࡍࡿ᫬㛫

(Tmax) ࡣᐇ㦂࡛ᚓࡽࢀࡓࢹ࣮ࢱࢆ᥇⏝ࡋࡓࠋࣂ࢖࢜࢔࣋࢖ࣛࣅࣜࢸ࢕ (BA) ࡣ⤒ཱྀᢞ୚࠾ࡼࡧ㟼⬦ෆ

ᢞ୚ᚋࡢ⏝㔞⿵ṇࡋࡓ↓㝈᫬㛫ࡲ࡛ࡢAUC (AUCinf) ࡢẚࡼࡾ⟬ฟࡋࡓࠋ

⤖⤖ᯝ 2.3 2.3.1 ࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾ࡅࡿᮍኚ໬యࡢ⾑₢୰ືែ TAK-357 ࢆࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡬ 1 mg/kg ࡢ⏝㔞࡛㟼⬦ෆᢞ୚ཪࡣࣛࢵࢺ࡬ 0.3, 1 ࠾ࡼࡧ 3 mg/kg ࡢ ⏝㔞࡛㸪࢖ࢾ࡬3 mg/kgࡢ⏝㔞࡛⤒ཱྀᢞ୚ࡋࡓᚋࡢ⾑₢୰⃰ᗘ᥎⛣ࢆFig. 2-1 ࡟♧ࡋࡓࠋࡲࡓ㸪TAK-357 ࡢ⸆≀ືែࣃ࣓࣮ࣛࢱࢆTable 2-1 ࡟♧ࡋࡓࠋࣛࢵࢺ࠾ࡼࡧ࢖ࢾࡢ CLp ࡣࡑࢀࡒࢀ 0.180 L/h/kg ࠾ࡼ ࡧ0.0237 L/h/kg ࡛࠶ࡾ㸪Vss ࡣࡑࢀࡒࢀ 33.5 L/kg ࠾ࡼࡧ 60.3 L/kg ࡛࠶ࡗࡓࠋ3 mg/kg ࡛ࣛࢵࢺ࠾ࡼࡧ ࢖ࢾ࡬⤒ཱྀᢞ୚ᚋࡢ⤊ᮎ┦ࡢt1/2ࡣࡑࢀࡒࢀ211 ᫬㛫 (⣙ 9 ᪥) ࠾ࡼࡧ 1420 ᫬㛫 (⣙ 60 ᪥) ࡛࠶ࡾ㸪 ⤒ཱྀᢞ୚ᚋࡢBA ࡣࡑࢀࡒࢀ 59.2%࠾ࡼࡧ 66.6%࡛࠶ࡗࡓࠋࣛࢵࢺࡢ Cmax࠾ࡼࡧAUCinfࡣ0.3-3 mg/kg ࡢ⏝㔞⠊ᅖ࡛࠾࠾ࡼࡑ⏝㔞ẚ࡟ᛂࡌࡓୖ᪼ࡀㄆࡵࡽࢀࡓࠋ

2.3.2 ⤌⧊ศᕸ

[14_{C]TAK-357 ࢆࣛࢵࢺ࡬3 mg/kg ࡛༢ᅇ⤒ཱྀᢞ୚ᚋ0.5, 2, 8, 24, 168, 336 ࠾ࡼࡧ672 ᫬㛫ᚋࡢ⤌⧊୰}

⥲ᨺᑕ⬟⃰ᗘࢆFig. 2-2 ࡟♧ࡍࠋ⥲ᨺᑕ⬟⃰ᗘࡣከࡃࡢ⤌⧊࡟࠾࠸࡚ᢞ୚ 2 ᫬㛫ᚋ࡟ Cmax࡟㐩ࡋࡓࠋ

(19)

୚8 ᫬㛫ᚋ࡟ Cmax࡟㐩ࡋࡓࠋ⭈࿘ᅖ⬡⫫ࡸ⢭ᕢ࿘ᅖ⬡⫫࡬ࡢ⥲ᨺᑕ⬟ࡢศᕸࡣ㐜ࡃᢞ୚24 ᫬㛫ᚋࡀ Tmax࡛࠶ࡗࡓࠋ᭱⤊ホ౯᫬Ⅼ࡛࠶ࡿᢞ୚672 ᫬㛫ᚋࡢ⬡⫫⤌⧊/⾑₢⃰ᗘẚࡣ࠾ࡼࡑ 500 ࡛࠶ࡗࡓࠋ ⸆ຠᶆⓗ㒊఩࡛࠶ࡿ⬻୰ࡢ⥲ᨺᑕ⬟⃰ᗘࡣヨ㦂ᮇ㛫ࢆ㏻ࡋ࡚⾑₢୰࡜ẚ㍑ࡋ࡚㧗࠿ࡗࡓࠋ⭈࿘ᅖ⬡⫫ ࢆ⬡⫫⤌⧊ࡢ௦⾲࡜ࡋ࡚௦ㅰ≀⤌ᡂศᯒࢆホ౯ࡋࡓ⤖ᯝ㸪⬡⫫⤌⧊୰ࡢᨺᑕ⬟ࡣ᭷ᶵ⁐፹(ࢡࣟࣟ࣍ ࣒ࣝ࡜࣓ࢱࣀ࣮ࣝࡢΰᾮ)࡟ࡼࡾ᏶඲࡟ᢳฟࡉࢀ㸪⥲ᨺᑕ⬟ࡢ 84.2-94.0%ࡣᮍኚ໬య࡛࠶ࡗࡓࠋ [14C]TAK-357ࢆ࢖ࢾ࡟3 mg/kgࡢ⏝㔞࡛⤒ཱྀᢞ୚672᫬㛫ᚋ࡟⤌⧊୰⥲ᨺᑕ⬟⃰ᗘࢆ ᐃࡋࡓ⤖ᯝ㸪ホ౯ࡋࡓ࠸ࡎࢀࡢ⤌⧊࡟࠾࠸࡚ࡶᨺᑕ⬟ࢆ᳨ฟࡋ㸪⭈࿘ᅖ⬡⫫୰ࡀ᭱ࡶ㧗࠸⃰ᗘ࡛࠶ࡗࡓ(Fig. 2-3)ࠋ ⬡⫫⤌⧊/⾑₢୰⃰ᗘẚࡣ⣙ 300 ࡛࠶ࡗࡓࠋ⬡⫫⤌⧊୰ࡢᨺᑕ⬟ࡣࢡ࣒ࣟࣟ࣍ࣝ࡜࣓ࢱࣀ࣮ࣝࡢΰᾮ ࡟ࡼࡾ᏶඲࡟ᢳฟࡉࢀ㸪⥲ᨺᑕ⬟ࡢ98.2%ࡣᮍኚ໬య࡛࠶ࡗࡓࠋ 2.3.3 ⾑⌫⛣⾜ In vitro ࡛ホ౯ࡋࡓࣛࢵࢺ㸪࢖ࢾ࠾ࡼࡧࣄࢺࡢ⾑⌫⛣⾜⋡ࡣࡑࢀࡒࢀ 14.3-15.1%㸪23.8-25.5%࠾ࡼࡧ 9.9-11.8%࡛࠶ࡾ㸪࠸ࡎࢀࡢ✀࡟࠾࠸࡚ࡶ 0.1-10 g/mL ࡢ⃰ᗘ⠊ᅖ࡛⃰ᗘ౫Ꮡᛶࡣㄆࡵࡽࢀ࡞࠿ࡗࡓ (Table 2-2)ࠋࣛࢵࢺ㸪࢖ࢾ࠾ࡼࡧࣄࢺࡢ⾑ᾮ/⾑₢୰⃰ᗘẚ (Rb) ࡣ 0.70, 0.66 ࠾ࡼࡧ 0.66 ࡛࠶ࡗࡓࠋ 2.3.4 ⾑₢⺮ⓑ⤖ྜ In vitro ࡛ホ౯ࡋࡓ࣐࢘ࢫ㸪ࣛࢵࢺ㸪࢖ࢾ࠾ࡼࡧࣄࢺࡢ⾑₢⺮ⓑ⤖ྜ⋡ࡣࡑࢀࡒࢀ 97.7%-98.0%㸪 98.3-98.5%㸪98.9-99.2%࠾ࡼࡧ 97.1-97.4%࡛࠶ࡾ㸪࠸ࡎࢀࡢ✀࡟࠾࠸࡚ࡶ 0.1-10 g/mL ࡢ⃰ᗘ⠊ᅖ࡛

⃰ᗘ౫Ꮡᛶࡣㄆࡵࡽࢀ࡞࠿ࡗࡓ (Table 2-3)ࠋ᭦࡟㸪HSA㸪AGP ࠾ࡼࡧ HSA ࡜ AGP ࡢΰᾮ࡟ᑐࡍࡿ

⺮ⓑ⤖ྜ⋡ࡣࡑࢀࡒࢀ98.7-99.3%㸪96.6-98.6%࠾ࡼࡧ 99.4%࡛࠶ࡗࡓࠋ

2.3.5 ⾑₢୰⤌ᡂ

[14_{C]TAK-357 ࢆࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡬ 3 mg/kg ࡢ⏝㔞࡛⤒ཱྀᢞ୚ᚋࡢ⾑₢୰௦ㅰ≀⤌ᡂࢆㄪ࡭ࡓ}

(20)

ࡢ⤊ᮎ┦༙ῶᮇࡣࣛࢵࢺ࡛212 ᫬㛫㸪࢖ࢾ࡛ 1070 ᫬㛫࡛࠶ࡗࡓࠋࣛࢵࢺ⾑₢୰ࡢ⥲ᨺᑕ⬟࠾ࡼࡧ TAK-357 ࡢ AUC0-168hࡣࡑࢀࡒࢀ20.2 μg·h/mL ࠾ࡼࡧ 12.8μg·h/mL ࡛࠶ࡗࡓࠋᮍኚ໬యࡣ⥲ᨺᑕ⬟ࡢ 63.0%࡛࠶ࡾ㸪ᮍྠᐃ௦ㅰ≀ࡀṧࡾࡢ 37.0%ࢆ༨ࡵࡿ࡜ィ⟬ࡉࢀࡓࠋ࢖ࢾ⾑₢୰ࡢ⥲ᨺᑕ⬟࠾ࡼࡧ TAK-357 ࡢ AUC0-168hࡣࡑࢀࡒࢀ41.3 μg·h/mL ࠾ࡼࡧ 38.3 μg·h/mL ࡛࠶ࡗࡓࠋᮍኚ໬యࡣ⥲ᨺᑕ⬟ࡢ 92.8%ࢆ༨ࡵ㸪ṧࡾࡢ 7.2%ࡣᮍྠᐃ௦ㅰ≀࡛࠶ࡗࡓࠋ 2.3.6 ᤼ἥ࠾ࡼࡧ᤼ἥ≀୰⤌ᡂ [14_{C]TAK-357 ࢆࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡬ 3 mg/kg ࡢ⏝㔞࡛⤒ཱྀᢞ୚ᚋࡢ⥲ᨺᑕ⬟ࡢ᤼ἥ࠾ࡼࡧ᤼ἥ≀} ୰ࡢ௦ㅰ≀⤌ᡂࢆㄪ࡭ࡓ (Table 2-4㸪2-5)ࠋ⣅୰⤌ᡂศᯒヨ㦂࡟࠾ࡅࡿ඾ᆺⓗࣛࢪ࢜ࢡ࣐ࣟࢺࢢ࣒ࣛ ࡣFig. 2-5B ࡟♧ࡍࠋࣛࢵࢺ࡬ᢞ୚ 672 ᫬㛫ᚋࡢ⣼✚ࡢᒀ୰࠾ࡼࡧ⣅୰᤼ἥ⋡ࡣࡑࢀࡒࢀᢞ୚㔞ࡢ 12.6%࠾ࡼࡧ 60.1%࡛࠶ࡗࡓࠋᢞ୚ 672 ᫬㛫ᚋࡢᒕయ୰࠿ࡽᢞ୚㔞ࡢ 24.3%ࡢᨺᑕ⬟ࡀᅇ཰ࡉࢀࡓࠋ ୍᪉㸪24 ᫬㛫ࡲ࡛ᅇ཰ࡋࡓ࿧Ẽ୰࡟ࡣᨺᑕ⬟ࡣ᳨ฟࡉࢀ࡞࠿ࡗࡓࠋ࢖ࢾ࡟࠾࠸࡚ࡣᢞ୚ 168 ᫬㛫ᚋ ࡲ࡛࡟ᢞ୚㔞ࡢ28.9%ࡢᨺᑕ⬟ࡋ࠿᤼ἥ≀୰࠿ࡽᅇ཰ࡉࢀࡎ㸪ᒀ୰࡟ 2.4%㸪⣅୰࡟ 26.6%࡛࠶ࡗࡓࠋ ࡲࡓ㸪ᢞ୚ᚋ312-336 ᫬㛫, 480-504 ᫬㛫࠾ࡼࡧ 648-672 ᫬㛫ࡢ㛫࡟ᅇ཰ࡉࢀࡓ⣅࠿ࡽࡣᨺᑕ⬟ࡀᅇ཰ ࡉࢀࡓࠋTAK-357 ᮍኚ໬యࡣᒀ୰࡟ࡣ᳨ฟࡉࢀ࡞࠿ࡗࡓࠋࣛࢵࢺ࠾ࡼࡧ࢖ࢾ⣅୰࡛ࡣ᤼ἥࡉࢀࡓᨺ ᑕ⬟ࡢ43.0%࠾ࡼࡧ 60.5%ࡀᮍኚ໬య࡛࠶ࡾ㸪ṧࡾࡣᮍྠᐃ௦ㅰ≀࡛࠶ࡗࡓࠋ ⪃⪃ᐹ 2.4 TAK-357 ࡣ㠀ᖖ࡟㧗⬡⁐ᛶࡢ⸆≀࡛࠶ࡾ㸪ᮏ◊✲࡟࠾࠸࡚ࡑࡢ≉ᚩⓗ࡞ ADME ≉ᛶࡀ᫂ࡽ࠿࡜࡞ ࡗࡓࠋࣛࢵࢺ࡟࠾ࡅࡿ⸆ຠ⏝㔞࡛࠶ࡿ3 mg/kg ࡛ࡢ⤒ཱྀᢞ୚ᚋࡢ BA ࡣࣛࢵࢺ㸪࢖ࢾ࡟࠾࠸࡚ 50-70% ࡛࠶ࡾ㸪Ⰻዲ࡞྾཰࡜ప࠸ึᅇ㏻㐣ຠᯝࡀ♧၀ࡉࢀࡓ (Table 2-1)ࠋ࡞࠾㸪࢖ࢾࡢ PK ࣃ࣓࣮ࣛࢱࡢ⟬

ฟ࡟࠶ࡓࡗ࡚ࡣእᤄࡉࢀࡓAUC ࡢ๭ྜࡀ㧗࠿ࡗࡓࠋAUC ࡢእᤄ⋡ࡀ㧗࠸ࡇ࡜ࡣ TAK-357 ࡢ࢖ࢾࡢ

PK ≉ᛶホ౯࡟୙☜ᐇᛶࢆ⏕ࡴྍ⬟ᛶࡀ⪃࠼ࡽࢀࡿࠋࡼࡗ࡚㸪ࡼࡾṇ☜࡞࢖ࢾ PK ࣃ࣓࣮ࣛࢱࡢ⟬ฟ

(21)

࡜࠸࠺㠀ᖖ࡟㛗࠸⤊ᮎ┦ࡢ⾑₢୰༙ῶᮇࢆ♧ࡋ࡚࠾ࡾ㸪ࡇࢀࡣప࠸CLp࠾ࡼࡧ㧗࠸Vssࡢ್ࡀ཯ᫎࡉ ࢀࡓ⤖ᯝ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡓࠋࣛࢵࢺࡼࡾࡶప࠸CLp࠿ࡘ㧗࠸Vssࢆ♧ࡍ࢖ࢾ࡟࠾࠸࡚ࡣ㸪ࡼࡾ㛗࠸ ༙ῶᮇࢆ♧ࡍ⤖ᯝ࡜࡞ࡗࡓࠋ[14_{C]TAK-357 ࢆ 3 mg/kg ࡛⤒ཱྀᢞ୚ᚋࡋࡓ㝿㸪ࣛࢵࢺ࡛ᢞ୚㔞ࡢ 72.7%} ࡀ4 㐌㛫࡛㸪࢖ࢾ࡛ᢞ୚㔞ࡢ 28.9%ࡀ 1 㐌㛫࡛᤼ἥࡉࢀࡿࡢࡳ࡛࠶ࡗࡓ (Table 2-4)ࠋ୍᪉㸪ࣛࢵࢺ࡟ ࠾࠸࡚ࡣᮍ᤼ἥࡢᨺᑕ⬟ࡀᒕయ࠿ࡽᅇ཰ࡉࢀࡓࠋࡇࢀࡽࡢ⤖ᯝࡣTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀㉁ࡀ㠀 ᖖ࡟㛗࠸᫬㛫యෆ࡟ṧᏑࡋ࡚࠸ࡿࡇ࡜♧၀ࡋ࡚࠸ࡿࠋࣛࢵࢺ࡟࠾ࡅࡿᢞ୚168 ᫬㛫ᚋࡲ࡛ࡢ᤼ἥ⋡ 52.9%ࡣ࢖ࢾ࡜ẚ㍑ࡋ࡚㧗࠿ࡗࡓࠋ࢖ࢾ࡟࠾࠸࡚ࣛࢵࢺ࡜ẚ㍑ࡋ࡚㧗࠸ᮍ᤼ἥ⋡ࢆ♧ࡋࡓ⤖ᯝࡣ㸪࢖ ࢾ࡟࠾ࡅࡿప࠸CLp㸪㧗࠸Vss㸪ࡑࡢ⤖ᯝ࡜ࡋ࡚ࡢ㛗࠸༙ῶᮇࢆ♧ࡋࡓࡓࡵ࡜⪃࠼ࡽࢀࡿࠋࠋࡇࡢࡼ ࠺࡞⸆≀ࢆ཯᚟ᢞ୚ࡋࡓࡋࡓ㝿࡟㸪యෆ࡬㧗⃰ᗘ⵳✚ࡀ᝿ᐃࡉࢀࡿࡇ࡜ࡸ㸪యෆ࠿ࡽ㝖ཤࡍࡿࡇ࡜ࡀ 㞴ࡋ࠸ࡇ࡜࠿ࡽ㸪㠀ᖖ࡟㛗࠸༙ῶᮇࢆ௓ࡋࡓయෆ࡬㛗ᮇṧᏑࢆ♧ࡍ⸆≀࡟ࡘ࠸࡚㸪Ᏻ඲ᛶࡢほⅬ࠿ࡽ ⮫ᗋヨ㦂ᐇ᪋࡟ᑐࡍࡿᠱᛕ࡜࡞ࡾ࠼ࡿࠋ ⤌⧊ศᕸヨ㦂࠿ࡽ㸪⬻ෆ⃰ᗘࡀ⾑₢୰⃰ᗘࡼࡾ㧗࠿ࡗࡓࡇ࡜ࡣᶆⓗ⤌⧊࡛࠶ࡿ⬻ෆ࡬ࡢⰋዲ࡞⛣ ⾜ࡀ♧၀ࡉࢀࡓ (Figs. 2-2㸪2-3)ࠋ୍᪉࡛㸪ᨺᑕ⬟ࡀᶆⓗ⤌⧊࡛ࡣ࡞࠸ࣛࢵࢺ࠾ࡼࡧ࢖ࢾࡢ⬡⫫⤌⧊࡟ 㧗⃰ᗘศᕸࡍࡿࡇ࡜ࡶ᫂ࡽ࠿࡜࡞ࡗࡓࠋ⬡⫫⤌⧊୰ࡢTmaxࡣ24 ᫬㛫࡜⾑₢୰ࡢ Tmax 2 ᫬㛫࡜ẚ㍑ࡋ ࡚ⴭࡋࡃ㐜࠿ࡗࡓࠋࡇࢀࡣTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀㉁ࡢ⬡⫫⤌⧊ࡢ⛣⾜ࡀ㐜ࡃ㸪ᐃᖖ≧ែ࡟㐩ࡍ ࡿࡲ࡛ࡢ᫬㛫ࡀ࠿࡞ࡾ㛗࠸ࡇ࡜ࢆ♧၀ࡋ࡚࠸ࡿࠋ⬡⫫⤌⧊୰ࡢ㐜࠸Tmaxࡣ㧗⬡⁐ᛶ⸆≀࡟ඹ㏻ࡋࡓ ⌧㇟࡛࠶ࡾ㸪ࡑࡢཎᅉࡣ⾑ᾮ࡜⬡⫫⤌⧊㛫ࡢ⛣⾜㐣⛬࡟࠾࠸࡚ᣑᩓࡀᚊ㏿࡜࡞ࡗ࡚࠸ࡿࡓࡵ࡜⪃࠼ࡽ ࢀ࡚࠸ࡿ (47)ࠋᢞ୚ 672 ᫬㛫ᚋ࡟࠾࠸࡚㸪⬡⫫⤌⧊/⾑₢୰⃰ᗘẚ 300-500 ࡜࠸࠺್ࡣ௚ࡢ⤌⧊࡜ẚ ㍑ࡋ࡚㠀ᖖ࡟㧗࠿ࡗࡓࠋࡇࡢ⃰ᗘẚࡣ௚ࡢ୍⯡ⓗ࡟▱ࡽࢀࡿ㧗⬡⁐ᛶ⸆≀ (ࢡࣟࣝࣉ࣐ࣟࢪࣥ: 41, ࣁ ࣟ࣌ࣜࢻ࣮ࣝ: 28㸪ࣃࣛࢳ࢜ࣥ: 101 ➼) ࡜ẚ㍑ࡋ࡚ࡶ㧗࠸ࡶࡢ࡛࠶ࡗࡓ (22, 35)ࠋ⤒ཱྀᢞ୚ 672 ᫬㛫(4 㐌㛫)ᚋ࡟࠾࠸࡚ࡶ⬡⫫⤌⧊୰⃰ᗘࡣࣛࢵࢺ࡛ 1 g equiv./g ௨ୖ㸪࢖ࢾ࡛10 g equiv./g ௨ୖ࡛࠶ࡗࡓࠋ ⬡⫫⤌⧊ࡢ⤌⧊㔜㔞ࡣࣛࢵࢺ࡛ࡣయ㔜ࡢ7-10%࡜ሗ࿌ࡉࢀ࡚࠸ࡿ (15)ࠋ୍᪉࡛㧗⃰ᗘࡢᨺᑕ⬟⃰ᗘ ࢆ♧ࡋࡓࡑࡢ௚ࡢ⤌⧊ࡢ㔜㔞ࡣ⓶⭵࡛య㔜ࡢ19%㸪๪⭈࡛ 0.019%㸪⫢⮚࡛ 3.66%㸪⮅⮚࡛ 0.32%࡛ ࠶ࡿࠋTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀㉁ࡢ⤌⧊୰ṧᏑ㔞ࡣ⤌⧊㔜㔞࡜⤌⧊୰ᨺᑕ⬟⃰ᗘࡢ᥃ࡅ⟬࡛⟬ฟ

(22)

ࡉࢀࡿࡓࡵ㸪ࣛࢵࢺ࡟࠾ࡅࡿTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀㉁ࡢṧᏑ㔞ࡣ⬡⫫⤌⧊୰࡛᭱ࡶ㧗ࡃ㸪௚ࡢ ⤌⧊ࡢ50 ಸ௨ୖ࡜⟬ฟࡉࢀࡓࠋ࢖ࢾ࡟࠾࠸࡚⬡⫫⤌⧊㔜㔞࡟㛵ࡍࡿ᝟ሗࡣᚓࡽࢀ࡞࠿ࡗࡓࠋࡋ࠿ࡋ ࡞ࡀࡽ㸪ࣅ࣮ࢢࣝ≟ࡢయ⬡⫫⋡ࡣ17-20%࡜ሗ࿌ࡉࢀ࡚࠸ࡿ (67)ࠋయ⬡⫫⋡ࡣ⬡⫫⤌⧊ࡔࡅ࡛࡞ࡃ㸪⾑ᾮ୰ࡸࡑࡢ௚ࡢ⤌⧊୰ࡢ⬡㉁㔞ࡶྵࢇࡔ್࡜⪃࠼ࡽࢀࡿࠋࡑࡇ࡛㸪ᮏ◊✲࡛ࡣ⬡⫫⤌⧊㔜㔞ࡣయ㔜 ࡢ15%࡜௬ᐃࡋ࡚⬡⫫⤌⧊୰ṧᏑ⋡ࢆィ⟬ࡋࡓࠋࡇࡢ௬ᐃࡢୗ࡛㸪࢖ࢾ⬡⫫⤌⧊୰ࡢ TAK-357 ࠾ࡼ ࡧࡑࡢ㛵㐃≀㉁ࡢṧᏑ㔞ࡣᢞ୚㔞ࡢ⣙50%࡛࠶ࡾ㸪⾑ᾮࡸ⫢⮚࡞࡝௚ࡢ⤌⧊ࡼࡾ 100 ಸ௨ୖ㧗࠸࡜ ᥎ᐃࡉࢀࡓࠋࡇࢀࡽࡢィ⟬⤖ᯝࡣࣛࢵࢺ࠾ࡼࡧ࢖ࢾ࡟࠾࠸࡚⬡⫫⤌⧊ࡀTAK-357 ࠾ࡼࡧࡑࡢ㛵㐃≀ ㉁ࡢ㈓ⶶᗜ࡜ࡋ࡚ᶵ⬟ࡋ࡚࠸ࡿࡇ࡜ࢆ♧ࡋ࡚࠸ࡿࠋ⬡⫫⤌⧊୰ࡢᨺᑕ⬟ࡢ⤌ᡂࡣ࡯ࡰTAK-357 ࡀ༨ ࡵࡓ (Fig.2-5C)ࠋࡉࡽ࡟㸪⬡⫫⤌⧊୰ࡢ TAK-357 ࠾ࡼࡧⱝᖸࡢ௦ㅰ≀ࡣ᭷ᶵ⁐፹࡟ࡼࡾ࡯ࡰ᏶඲࡟ ᢳฟࡉࢀࡓࡓࡵ㸪ࡇࢀࡽࡣ⬡⫫⤌⧊୰ࡢᡂศ࡟ඹ᭷⤖ྜࡋ࡚࠸࡞࠸ࡇ࡜ࡀ♧၀ࡉࢀࡓࠋࡇࢀࡽࡢ⤖ᯝ ࠿ࡽ㸪TAK-357 ཬࡧࡑࡢ⏤᮶ᡂศࡀ⬡⫫⤌⧊୰ࡢ㧗⃰ᗘᏑᅾࡍࡿ⌧㇟ࡣ㸪TAK-357 ࡢ≀⌮໬Ꮫⓗᛶ ㉁࡟ࡼࡿࡶࡢ࡛࠶ࡿ࡜⪃࠼ࡽࢀ㸪ྠᵝࡢഴྥࡣࣄࢺ࡟࠾࠸࡚ࡶㄆࡵࡽࢀࡿ࡜⪃࠼ࡽࢀࡓࠋ In vitro ࡟࠾ࡅࡿ⾑⌫⛣⾜⋡ࡣ࠸ࡎࢀࡢ✀࡟࠾࠸࡚ࡶపࡃ㸪୍᪉࡛⾑₢⺮ⓑ⤖ྜ⋡ࡣ㧗࠿ࡗࡓࡀ㸪 ⾑⌫⛣⾜㸪⾑₢⺮ⓑ⤖ྜ࡜ࡶ⃰ᗘ౫Ꮡᛶࡣㄆࡵࡽࢀ࡞࠿ࡗࡓ (Table 2-2, 2-3)ࠋ୍㒊ࡢ⸆≀࡟࠾࠸࡚⾑ ⌫⛣⾜⋡ࡀ㧗ࡃ㸪⾑⌫ࡀ⸆≀ࡢ㈓ⶶᗜ࡜ࡋ࡚ᶵ⬟ࡍࡿࡇ࡜࡛⾑₢࠿ࡽࡢ㛗࠸ᾘኻ༙ῶᮇࢆច㉳ࡍࡿࡇ

࡜ࡀ▱ࡽࢀ࡚࠸ࡿ (38)ࠋࡋ࠿ࡋ࡞ࡀࡽ㸪TAK-357 ࡟ࡘ࠸࡚ࡣin vitro ࡟࠾ࡅࡿ⾑⌫⛣⾜⋡ࡢ⤖ᯝ࠿ࡽ㸪

⾑⌫࡬ࡢ⛣⾜ࡀ⾑₢࠿ࡽࡢᾘኻ༙ῶᮇ࡟ཬࡰࡍᙳ㡪ࡣᑠࡉ࠸࡜⪃࠼ࡽࢀࡓࠋ୍᪉㸪TAK-357 ࡣࣄࢺ ⾑₢୰࡛HSA࡜AGPࡢ୧᪉࡟ᙉࡃ⤖ྜࡋ㸪ࡇࢀࡣప࠸CLp࡟࠶ࡿ⛬ᗘᐤ୚ࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀࡓࠋ Table 2-5 ࡟♧ࡉࢀ࡚࠸ࡿࡼ࠺࡟㸪TAK-357 ⤒ཱྀᢞ୚ᚋ࡟ࣛࢵࢺ࠾ࡼࡧ࢖ࢾᒀ୰࡟ࡣᮍኚ໬యࡣ᳨ ฟࡉࢀ࡞࠿ࡗࡓࠋࣛࢵࢺࡢ⣅୰࡛ࡣᢞ୚ᨺᑕ⬟㔞ࡢ18.6%ࡀ᤼ἥࡉࢀ㸪᤼ἥࡉࢀࡓ⥲ᨺᑕ⬟ࡢ 43.0% ࡀᮍኚ໬య࡛࠶ࡗࡓࠋࡲࡓ㸪࢖ࢾࡢ⣅୰࡛ࡣᢞ୚ᨺᑕ⬟㔞ࡢ16.1%ࡀ᤼ἥࡉࢀ㸪᤼ἥࡉࢀࡓ⥲ᨺᑕ⬟ ࡢ60.5%ࡀᮍኚ໬య࡛࠶ࡗࡓࠋࣛࢵࢺ࠾ࡼࡧ࢖ࢾࡢ BA ࡀࡑࢀࡒࢀ 60%࠾ࡼࡧ 67%࡛࠶ࡿࡇ࡜ࢆ⪃៖ ࡍࡿ࡜㸪ࡇࡢ⣅୰ᮍኚ໬య⏬ศࡣ⤒ཱྀᢞ୚ᚋࡢᮍ྾཰ᡂศࢆྵࢇ࡛࠸ࡿ࡜⪃࠼ࡽࢀࡿࠋࡲࡓ㸪⣅୰ᨺ

(23)

ᑕ⬟ࡢ40-60%࠾ࡼࡧᒀ୰ࡢ඲࡚ࡢ⏬ศࡣᮍྠᐃࡢ௦ㅰ≀࡛࠶ࡗࡓࡇ࡜࠿ࡽ㸪ᑡ࡞ࡃ࡜ࡶヨ㦂ᮇ㛫ෆ

࡟࠾࠸࡚ࡣ྾཰ࡉࢀࡓTAK357 ࡢ୺࡞ᾘኻ⤒㊰ࡣ௦ㅰ࡛࠶ࡿࡇ࡜ࡀ♧၀ࡉࢀࡓࠋ

TAK-357 ࡜ྠᵝࡢ ADME ≉ᛶࡣ 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) ࡞࡝ࡢ࣏ࣜሷ໬ࣅࣇ࢙ࢽࣝ (PCBs) ࡛ࡶㄆࡵࡽࢀ࡚࠾ࡾ㸪6-CB ࡣ⬡⫫⤌⧊࡟㠀ᖖ࡟ࡼࡃศᕸࡋ㸪᤼ἥࡣ㠀ᖖ࡟㐜࠸ (54)ࠋࡲࡓ㸪 6-CB ࡢ⬡⫫⤌⧊୰࠿ࡽࡢᾘኻࡸࣛࢵࢺࡢయෆ࠿ࡽࡢ᤼ἥࡣ㣗㣵ไ㝈࡟ࡼࡿ⬡⫫⤌⧊ࡢῶᑡ࡟ࡼࡗ࡚ ຍ㏿ࡉࢀࡿ (37, 64, 65)ࠋࡇࡢ≧ἣୗ࡛⾑୰⃰ᗘࡣୖ᪼ࡋ࡚࠾ࡾ㸪ࡇࢀࡣ≀㉁ࡀ⬡⫫⤌⧊୰࠿ࡽ⾑ᾮ୰ ࡬෌ศᕸࡋࡓࡇ࡜ࢆ཯ᫎࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀࡿࠋࡇࢀࡽࡢᩥ⊩᝟ሗࡣ㠀ᖖ࡟㧗⬡⁐ᛶ⸆≀ࡢయෆືែ ࡣయ⤌ᡂ㸪≉࡟⬡⫫⤌⧊㔜㔞࡟ᙳ㡪ࢆཷࡅࡿࡇ࡜ࢆ♧၀ࡋ࡚࠸ࡿࠋGeyer ࡽࡣ⬡⫫⤌⧊ࡀ㈓ⶶ⤌⧊࡜ ࡋ࡚ᶵ⬟ࡋ㸪⾑ᾮ୰⃰ᗘࢆపୗࡉࡏࡿࡇ࡜࡟ࡼࡾ㸪௚ࡢࡼࡾᩄឤ࡞⤌⧊ࢆẘ≀࠿ࡽಖㆤࡋ࡚࠸ࡿ࡜ホ ౯ࡋ࡚࠸ࡿ (26)ࠋయ⬡⫫ࡀῶᑡࡋࡓ㝿࡟ࡣ㧗⬡⁐ᛶ⸆≀ࡣ୍᫬ⓗ࡞⾑୰⃰ᗘࡢୖ᪼ࢆ⤒࡚㸪᤼ἥࡣ ㏿ࡃ࡞ࡿ࡜⪃࠼ࡽࢀࡿࠋࡇࡢ୍᫬ⓗ࡞⸆≀ࡢ⾑୰⃰ᗘୖ᪼ࡀᏳ඲ᛶୖၥ㢟࡜࡞ࡿሙྜ࡟ࡣ㸪⸆≀ࡣయ ෆṧᏑࡍࡿࡶࡢࡢయ⬡⫫ࡣ୍ᐃ࡟ಖࡘ࡭ࡁ࡜⪃࠼ࡽࢀࡿࠋࡇࢀࡽࡢ᝟ሗࢆ຺᱌ࡍࡿ࡜㸪TAK-357 ࡢ ⮫ᗋ㛤Ⓨ࡛ࡣయ⬡⫫㔞ࡢኚ໬ࢆほᐹࡋ㸪య⬡⫫㔞ࡢኚ໬࡟ࡼࡗ࡚඲㌟ᭀ㟢ࡀኚ໬ࡍࡿࡇ࡜࠿ࡽ㸪Ᏻ඲ ᛶ࣐࣮ࢪࣥࢆὀព῝ࡃ☜ㄆࡍ࡭ࡁ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡓࠋୖグࡢ⤖ᯝ࡞ࡽࡧ࡟⪃ᐹ࠿ࡽ㸪TAK-357 ࡢ ⾑₢୰⃰ᗘ࡜య㔜ኚ໬ࡢ㛵ಀ࡟ࡘ࠸࡚ࡢ᭦࡞ࡿᐃ㔞ⓗ࡞ゎᯒࡀ㸪⮫ᗋヨ㦂᮲௳ࡢ᭱㐺໬ࡸࡑࡢ⤖ᯝゎ㔘࡟㔜せ࡜⪃࠼ࡽࢀࡓࠋ ᑠᑠᣓ 2.5

ᮏヨ㦂࡛ࡣTAK-357 ࡢື≀࡟࠾ࡅࡿ ADME ≉ᛶࢆ᫂ࡽ࠿࡜ࡋࡓࠋTAK-357 ࡣ㧗⃰ᗘ࡟⬡⫫⤌⧊

࡟ศᕸࡋ㸪ࡑࡢ⤖ᯝ㛗࠸⾑₢୰༙ῶᮇ࡜యෆ࡬ࡢ⵳✚ࢆ㉳ࡇࡋ࡚࠸ࡿࡇ࡜ࡀ♧၀ࡉࢀࡓࠋࡲࡓ㸪 TAK-357 ࡢయෆືែࡣື≀࠾ࡼࡧࣄࢺ࡟࠾࠸࡚⬡⫫㔜㔞ኚ໬࡟ࡼࡗ࡚ᙳ㡪ࢆཷࡅࡿࡇ࡜ࡀ♧၀ࡉࢀ ࡓࠋ

(24)

⬡⫫⤌⧊࡬㧗⃰ᗘศᕸࡍࡿ⸆≀ࡢయෆືែ࡟୚࠼ࡿᛴ⃭࡞య㔜పୗࡢᙳ㡪

:

➨

3❶

⏕⌮Ꮫⓗ⸆≀ືែ

(PBPK) ࣔࢹࣜࣥࢢ&ࢩ࣑࣮ࣗࣞࢩࣙࣥ

ࡣࡌࡵ࡟ 3.1 ᮏ❶࡛ࡣ㸪➨1 ❶࡛㏙࡭ࡓ࢖ࢾࡢ TK ヨ㦂᫬ࡢ᭱⤊ᢞ୚ 2 㐌㛫ᚋ࠿ࡽㄆࡵࡽࢀࡓ TAK-357 ࡢ⾑₢ ୰⃰ᗘୖ᪼ࡢཎᅉ࡟ࡘ࠸࡚᥎ᐹࡋࡓࠋ➨2 ❶࡛ࡣ㧗⬡⁐ᛶ⸆≀࡛࠶ࡿ TAK-357 ࡢ㠀⮫ᗋ ADME ≉ᛶ ࡟ࡘ࠸࡚ホ౯ࡋ㸪㠀ᖖ࡟㛗࠸༙ῶᮇ࡜⬡⫫⤌⧊࡬ࡢ㧗⃰ᗘࡢศᕸࢆ᫂ࡽ࠿࡟ࡋࡓ (27)ࠋPCB ࡸ࣏ࣜ ሷ໬ࢪ࣋ࣥࢰ-p-ࢪ࢜࢟ࢩࣥ (PCDDs) ࡞࡝ࡢ㧗⬡⁐ᛶẘᛶ≀㉁ࡣ㸪TAK-357 ࡜ྠᵝࡢ≉ᛶࡀሗ࿌ࡉ ࢀ࡚࠸ࡿ (34)ࠋPCB ࡢ 1 ✀࡛࠶ࡿ 6-CB ࡣ⬡⫫⤌⧊࡬ࡢศᕸࡀ㠀ᖖ࡟ከࡃ㸪⾑୰༙ῶᮇࡀ 100 ᪥௨ୖ ࡜ࡑࡢᾘኻࡀ㠀ᖖ࡟㐜࠸ (54)ࠋࡇࡢ 6-CB ࡣᦤ㣵ไ㝈࡟ࡼࡿ㣚㣹≧ែ࡟࠾࠸࡚㸪⬡⫫⤌⧊࠿ࡽࡢᾘኻ ࡸయෆ࠿ࡽࡢ᤼ἥࡀຍ㏿ࡍࡿሗ࿌ࡀ࠶ࡿ (37, 64, 65)ࠋࡇࡢ≧ἣୗ࡛⾑୰ 6-CB ⃰ᗘࡣ㧗್ࢆ♧ࡋ࡚࠸ ࡿࡇ࡜࠿ࡽ⬡⫫⤌⧊୰࠿ࡽ⾑୰࡬ࡢ෌ศᕸࡀ♧၀ࡉࢀ࡚࠸ࡿࠋ6-CB ࡛ࡢሗ࿌࠾ࡼࡧ TAK-357 ࡢ ADME ≉ᛶ࠿ࡽ࢖ࢾ⬡⫫⤌⧊୰࡟ṧᏑࡋࡓTAK-357 ࡀయ㔜ῶᑡ࡟క࠸⾑₢୰࡬෌ศᕸࡋࡓྍ⬟ᛶࡀ ⪃࠼ࡽࢀࡓࠋࡋ࠿ࡋ࡞ࡀࡽ㸪㣚㣹ࡸឤᰁ࡟ࡼࡿᛴ⃭࡞య㔜పୗࡢ෌⌧ࡣື≀೔⌮ୖၥ㢟࡛࠶ࡿࠋࡑࡇ ࡛ᮏ❶࡛ࡣ㸪᪤ᏑࡢPK ࢹ࣮ࢱࢆ⏝࠸ࡓᐃ㔞ⓗ࡞ゎᯒ᪉ἲ࡜ࡋ࡚⏕⌮Ꮫⓗ⸆≀ືែ(PBPK)ࣔࢹࣜࣥࢢ &ࢩ࣑࣮ࣗࣞࢩࣙࣥ(M&S)ࢆ⏝࠸ࡓࠋPBPK M&S ࡣࣄࢺ PK ண (24)㸪⸆≀㛫┦஫స⏝ண (39)㸪 ⤌⧊୰⸆≀⃰ᗘண (32) ࠾ࡼࡧᏳ඲ᛶヨ㦂࡟࠾ࡅࡿࣜࢫࢡホ౯➼ (49) ࡟⏝࠸ࡽࢀ࡚࠸ࡿࠋࡲࡓ㸪 PCB ࡸ tetrachlorobenzyltoluenes ࡞࡝ࡢ⎔ቃẘ⣲ࡢ PBPK ゎᯒࡶሗ࿌ࡉࢀ࡚࠸ࡿ (42, 50)ࠋᮏ◊✲࡛ࡣ TAK-357 ࡟ࡘ࠸࡚㸪ࡑࡢయෆືែࢆ⾲⌧ࡍࡿࡓࡵࡢ᭱ᑠᵓᡂࡢ PBPK ࣔࢹࣝࢆᵓ⠏ࡋ㸪TAK-357 ࡢ ⾑₢୰⃰ᗘୖ᪼࡟ࡘ࠸࡚ホ౯ࡋࡓࠋ ᐇ㦂ᮦᩱ࡜᪉ἲ 3.2 3.2.1 ⿕㦂≀㉁㸪ヨ⸆ TAK-357 ࡣṊ⏣⸆ရᕤᴗᰴᘧ఍♫㸪〇⸆◊✲ᡤ࡛ྜᡂࡉࢀࡓࡶࡢࢆ⏝࠸ࡓࠋࡑࡢ௚ࡢヨ⸆࡜ヨᾮ ࡣศᯒࢢ࣮ࣞࢻࡢࡶࡢࢆ㉎ධࡋࡓࠋ

(25)

3.2.2 ື≀

㞝ᛶࣅ࣮ࢢࣝ≟ (13, 19 ࣨ᭶㱋㸪ᢞ୚㛤ጞ᫬ 10.5, 11.8 kg) ࡣ໭ᒣࣛ࣋ࢫࡼࡾධᡭࡋࡓࠋ࢖ࢾࡣࢫࢸ ࣥࣞࢫࢣ࣮ࢪ࡛㣫⫱ࡋ㸪1 ᪥ 1 ᅇ࣌ࣞࢵࢺ≧ࡢ㣵 Certificate canine diet #5007 (PMI Nutrition International, ࢝ࣥࢨࢫ) ࡀ⤥㣵ࡉࢀ㸪Ỉࡣ⮬⏤ᦤỈ࡜ࡋࡓࠋヨ㦂ᮇ㛫୰ṇᖖ࡛࠶ࡗࡓಶయࢆ No.1 ࡜ࡋ㸪᭱⤊ᢞ୚ 2 㐌㛫ᚋࡼࡾయ㔜పୗࡀㄆࡵࡽࢀࡓಶయࢆNo.2 ࡜ࡋࡓࠋ 3.2.3 ື≀ヨ㦂 ๓㏙ࡋࡓ⾑₢୰⃰ᗘୖ᪼ࡣணഛⓗ࡞TK ࠾ࡼࡧᏳ඲ᛶホ౯ࡢࡓࡵ࡟⾜ࢃࢀࡓヨ㦂ࡢ⤖ᯝ࡛࠶ࡾ㸪ᐇ 㦂᪉ἲࡣ௨ୗࡢ㏻ࡾ࡛࠶ࡿࠋTAK-357 ࡣ 0.5%࣓ࢳࣝࢭ࣮ࣝࣟࢫ⁐ᾮ࡟ᠱ⃮ࡋࡓࠋTAK-357 ࡣ 1 ᪥ 1 ᅇ࡛15 ᪥㛫 2 㢌ࡢ࢖ࢾ࡟ 1000 mg/kg ࡢ⏝㔞࡛⤒ཱྀᢞ୚ࡋࡓࠋࢥࣥࢺ࣮ࣟࣝ⩌࡟ࡣᢞ୚፹యࢆᢞ୚ࡋ ࡓࠋ㣗㣵ࡣᢞ୚2 ᫬㛫ᚋ࡟⤥㣵ࡋࡓࠋTAK-357 ⾑₢୰⃰ᗘ ᐃ⏝ࡢ᥇⾑ࡣ㸪ึᅇᢞ୚ 1㸪2㸪4㸪8㸪 24 ᫬㛫ᚋ㸪15 ᅇ┠ᢞ୚ࡢᢞ୚๓㸪ᢞ୚ 1㸪2㸪4㸪8㸪24㸪48㸪72 ᫬㛫ᚋ࠾ࡼࡧ 15 ᅇ┠ᢞ୚ࡢ 7㸪14㸪 21㸪28 ᪥ᚋ࡟ᐇ᪋ࡋࡓࠋయ㔜 ᐃࡣ Day 0 (ᢞ୚㛤ጞ᪥) ࠿ࡽ Day 42 ࡲ࡛ 1 㐌㛫࡟ 1 ᅇ⾜ࡗࡓࠋ඲࡚ ࡢື≀ヨ㦂ࡣṊ⏣⸆ရᕤᴗᰴᘧ఍♫Institutional Animal Care and Use Committee (IACUC) ࡟࡚ホ౯㸪ᢎ ㄆࡉࢀࡓࠋ

3.2.4 ⾑₢୰ TAK-357 ࡢᐃ㔞

⾑₢ヨᩱ୰ࡢTAK-357 ࡣ HPLC ࢆ⏝࠸࡚ᐃ㔞ୗ㝈 0.025 g/mL ࡢᐃ㔞ἲ࡛ ᐃࡋࡓࠋ⾑₢ヨᩱࡣ

࣓ࢱࣀ࣮࡛ࣝ㝖⺮ⓑࡋ㸪㐲ᚰୖΎࢆ20 mmol/L ࡢ㓑㓟࢔ࣥࣔࢽ࣒࢘Ỉ⁐ᾮ࡛ᕼ㔘ࡋࡓᚋ㸪40°C ࡟タ

ᐃࡋࡓACQUITY UPLC HSS T3 ࣒࢝ࣛ (1.8 m, 2.1 × 100 mm, Waters) ࢆ᥋⥆ࡋࡓHPLC ࡟ὀධࡋࡓࠋ

᳨ฟ࡟ࡣ⺯ග᳨ฟჾࢆ⏝࠸㸪ບ㉳Ἴ㛗ࡀ290 nm㸪᳨ฟἼ㛗ࡀ 760 nm ࡛ ᐃࡋࡓࠋ࢔ࢭࢺࢽࢺࣜࣝ/

࣓ࢱࣀ࣮ࣝ/20 mmol/L 㓑㓟࢔ࣥࣔࢽ࣒࢘ࡀ 9:9:2 (v/v/v) ࡢᆒ୍⃰ᗘࡢ⛣ື┦࡛ 3 ศ㛫࠿ࡅ࡚ὶ㏿ 0.5 mL/min ࡛ࢡ࣐ࣟࢺࢢࣛࣇศ㞳ࢆ⾜ࡗࡓࠋ

(26)

3.2.5 PBPK ࣔࢹࣜࣥࢢ

➨2 ❶࡛ሗ࿌ࡋࡓTAK-357 ࢆࣛࢵࢺ࡬0.3, 1, 3 mg/kg ࡢ⏝㔞࡛⤒ཱྀᢞ୚ཪࡣ1 mg/kg ࡢ⏝㔞࡛㟼⬦

ෆᢞ୚࠾ࡼࡧ࢖ࢾ࡬3 mg/kg ࡢ⏝㔞࡛⤒ཱྀᢞ୚㸪1 mg/kg ࡢ⏝㔞࡛㟼⬦ෆᢞ୚ࡋࡓᚋࡢ⾑₢୰⃰ᗘ᥎

⛣ࢆPBPK ࣔࢹࣝᵓ⠏࡟⏝࠸ࡓ (27)ࠋࣔࢹࣜࣥࢢ࡟ࡣ NONMEM VI (ICON Development Solution, ࣓ ࣮ࣜࣛࣥࢻ)ࡢ First-order Conditional Estimation (FOCE) with interaction ἲࢆ⏝࠸ࡓࠋࣃ࣓࣮ࣛࢱ᥎ᐃࡢ ཰᮰ᇶ‽࡜ࡋ࡚ࡣ᭷ຠᩘᏐ3 ᱆ࢆ⏝࠸ࡓࠋCompaq Digital Fortran Version 6.1 ࢆ NONMEM ࢆᐇ⾜ࡍࡿ ࡓࡵࡢࢥࣥࣃ࢖࣮ࣛ࡜ࡋ࡚⏝࠸ࡓࠋࢩ࣑࣮ࣗࣞࢩࣙࣥ࡟ࡣBerkeley Madonna Ver 8.3.8 (University of California, ࢝ࣝࣇ࢛ࣝࢽ࢔) ࢆ⏝࠸ࡓࠋࢃࡎ࠿࡞ಶయ㛫ᕪ᥎ᐃࡢ೫ࡾࡀࢹ࣮ࢱࣇ࢕ࢵࢸ࢕ࣥࢢ࡟୙㐺 ษ࡞ຠᯝࢆ୚࠼ࡿࡓࡵ㸪ᮏゎᯒ࡛ࡣಶయ㛫ኚືࢆホ౯ࡋ࡞࠿ࡗࡓࠋṧᕪホ౯࡟ࡣୗグࡢ┦ᑐㄗᕪࣔࢹ ࣝࢆ⏝࠸ࡓ (ᘧ 3-1)ࠋ

, = , × 1 + ᘧ3-1

ࡇࡇ࡛㸪Yobs,ij ࡣ i ␒ࡢಶయࡢ j ␒┠ࡢᐇ ್㸪Ypred,ijࡣࣔࢹࣝ࠿ࡽィ⟬ࡉࢀࡓண ್㸪ij,ࡣண ್ ࡜ᐇ ್ࡢṧᕪࢆ⾲ࡍࠋ_ijࡣᖹᆒ0㸪ศᩓ 2_{ࡢṇつศᕸࢆ௬ᐃࡋࡓࠋࣔࢹࣝ㑅ᢥࡣ}_{goodness-of-fit plot㸪} ࣃ࣓࣮ࣛࢱ᥎ᐃࡢ⢭ᗘ㸪᭱ᑠ┠ⓗ㛵ᩘ್ (MVOF) ࢆᇶ࡟ᐇ᪋ࡋࡓࠋ Fig. 3-1 ࡟᭱⤊ⓗ࡟ᵓ⠏ࡋࡓ PBPK ࣔࢹࣝᅗࢆ♧ࡍࠋࣔࢹࣝࡣ 4 ࡘࡢ⤌⧊ࢥࣥࣃ࣮ࢺ࣓ࣥࢺ࡜⾑ᾮ ࢥࣥࣃ࣮ࢺ࣓ࣥࢺ࡟࡚ᵓᡂࡉࢀ㸪TAK-357 ࡢ⾑₢୰ PK ࢆࡼࡃグ㏙ྍ⬟࡛࠶ࡗࡓࠋ⓶⭵ࢥࣥࣃ࣮ࢺ࣓ ࣥࢺ࡜ṧ⤌⧊ࢥࣥࣃ࣮ࢺ࣓ࣥࢺࡢᇶᮏࡢᚤศᘧࡣ௨ୗࡢ࡜࠾ࡾ࡛࠶ࡿ (ᘧ 3-2, 3-3)ࠋ = × ᘧ3-2 C = ᘧ3-3

ࡇࡇ࡛Ctissue㸪Cblood㸪Ptissue㸪Qtissue㸪Vtissue࠾ࡼࡧAtissueࡣ㸪ࡑࢀࡒࢀ⤌⧊୰TAK-357 ⃰ᗘ㸪⾑ᾮ୰ TAK-357 ⃰ᗘ㸪⤌⧊/⾑ᾮศ㓄ಀᩘ, ᒁᡤⓗ⾑ὶ㏿ᗘ㸪⤌⧊య✚࠾ࡼࡧ⤌⧊୰ TAK-357 㔞ࢆ⾲ࡍࠋ⾑₢୰ TAK-357 ⃰ᗘ (Cplasma) ࡣᘧ 3-4 ࡢࡼ࠺࡟ィ⟬ࡋࡓࠋ

(27)

ࡇࡇ࡛Rb ࡣ⾑ᾮ/⾑₢⃰ᗘẚࢆ⾲ࡋ㸪ࡇࡢ್ࡣ➨ 2 ❶࡛⟬ฟࡋࡓ್ࢆ⏝࠸ࡓࠋ

➨2❶࡛ᐇ᪋ࡋࡓADME≉ᛶホ౯ࡢ⤖ᯝ࠿ࡽᮏゎᯒ࡟࠾࠸࡚ࡣTAK-357ࡢᾘኻࡣ⫢⮚࡛ࡢ௦ㅰ࡟

ࡼࡿࡶࡢ࡜௬ᐃࡋ㸪⫢⮚ࢥࣥࣃ࣮ࢺ࣓ࣥࢺࡣᘧ3-5 ࡢࡼ࠺࡟グ㏙ࡋࡓࠋ

= × CL × + × × ᘧ3-5

ࡇࡇ࡛㸪AdoseࡣTAK-357 ࡢᢞ୚㔞㸪CLintࡣ⫢ᅛ᭷ࢡࣜ࢔ࣛࣥࢫ (㠀⤖ྜᆺศ⋡࠾ࡼࡧ Rb ྵࡴ)㸪

Kaࡣ྾཰㏿ᗘᐃᩘ㸪F ࡣ࢔࣋࢖ࣛࣅࣜࢸ࢕ࢆ♧ࡍࠋKa㸪CLint࠾ࡼࡧF ࡣࣇ࢕ࢵࢸ࢕ࣥࢢ࡟ࡼࡾ᥎ᐃ ࡋࡓࠋ ⬡⫫⤌⧊࡛ࡣୗグࡢᘧࢆ⏝࠸ࡓ (ᘧ 3-6, 3-7)ࠋ = × × × ᘧ3-6 = × × ᘧ3-7 ⬡⫫⤌⧊࡟࠾࠸࡚ࡣᣑᩓᚊ㏿ࢆ⪃៖ࡋࡓࠋᘧ3-6 ࡟࠾ࡅࡿ DIF ࡣᣑᩓ㏿ᗘᐃᩘ (Qfat࡟ᑐࡍࡿẚ࡜ ࡋ࡚⟬ฟ)㸪Cvfࡣ⬡⫫⤌⧊ࡢᚤᑠ⾑⟶୰TAK-357 ⃰ᗘࢆ⾲ࡍࠋࣛࢵࢺࡢ DIF ࡣࣇ࢕ࢵࢸ࢕ࣥࢢ࡟ࡼ ࡗ࡚᥎ᐃࡋࡓࠋ࢖ࢾ࡟࠾࠸࡚ࡣDIF ࡣࣔࢹࣜࣥࢢࡢ㐣⛬࡛኱ࡁ࠸್࡜᥎ᐃࡉࢀࡓࡓࡵ 10 ࡟ᅛᐃࡋࡓࠋ ⏕⌮Ꮫⓗࣃ࣓࣮ࣛࢱ (⤌⧊య✚࠾ࡼࡧ⾑ὶ㏿ᗘ) ࡣᩥ⊩್ࢆᘬ⏝ࡋࡓ (15, 56)ࠋࣛࢵࢺࡢ⤌⧊/⾑ᾮศ 㓄ಀᩘࡢึᮇ್ࡣ⬡⁐ᛶ࠿ࡽࡢ᥎ᐃ್ࢆ⏝࠸ࡓࠋ⫢⮚࠾ࡼࡧ⓶⭵࡟࠾ࡅࡿ⤌⧊/⾑ᾮศ㓄ಀᩘࡣࣛࢵ ࢺ࡟࠾ࡅࡿᐇ ࡢ⤌⧊㸪⾑ᾮ୰AUC ࡢẚ࠿ࡽ⟬ฟࡋࡓ್࡟ᅛᐃࡋࡓࠋ⬡⫫⤌⧊࡜ṧ⤌⧊ࡢ⤌⧊/⾑ᾮ ศ㓄ಀᩘࡣࣇ࢕ࢵࢸ࢕ࣥࢢ࠿ࡽ᥎ᐃࡋࡓࠋ⫢⮚ࡸ⭈⮚࡞࡝ࡢᾘኻ⮚ჾ࡟࠾ࡅࡿ⤌⧊/⾑ᾮศ㓄ಀᩘࡣ ⌮ㄽⓗ࡟ࡣ㠀ᢳฟ⋡ (Fh➼) ࡛⿵ṇࡍࡿᚲせࡀ࠶ࡿࠋࡋ࠿ࡋ࡞ࡀࡽ㸪TAK-357 ࡣ㠀ᖖ࡟ప࠸ࢡࣜ࢔ࣛ ࣥࢫࢆ♧ࡍࡓࡵ㸪⫢⮚࡟࠾ࡅࡿᢳฟ⋡ࡣ㠀ᖖ࡟ప࠸࡜᥎ᐹࡉࢀࡿࠋࡼࡗ࡚ᐇ ࡢAUC ẚࢆࡑࡢࡲࡲ ⫢⮚ࡢ⤌⧊/⾑ᾮศ㓄ಀᩘ࡜ࡋ࡚⏝࠸ࡓࠋ⤌⧊/⾑ᾮศ㓄ಀᩘࡣ⸆≀ࡢ≀⌮໬Ꮫⓗᛶ㉁࡟౫Ꮡࡍࡿࡓࡵ㸪 ࢖ࢾPBPK ࣔࢹࣝ࡟࠾ࡅࡿ⤌⧊/⾑ᾮศ㓄ಀᩘࡣࣛࢵࢺࡢ್࡜ྠࡌࡶࡢࢆ⏝࠸ࡓࠋ

(28)

3.2.6 ࢩ࣑࣮ࣗࣞࢩࣙࣥ

ᵓ⠏ࡋࡓPBPK ࣔࢹࣝࢆ⏝࠸࡚ⴭࡋ࠸య㔜పୗᚋࡢ࢖ࢾ TK ࢆࢩ࣑࣮ࣗࣞࢺࡋࡓࠋF ࡜ Kaࡣప⁐

ゎᛶࡢ⸆≀≉ᛶ࡜㧗⏝㔞ࡢヨ㦂࡛࠶ࡿࡇ࡜࠿ࡽ㸪ึᅇᢞ୚᫬࠾ࡼࡧヨ㦂ᮇ㛫୰ṇᖖ≧ែ࡛࠶ࡗࡓ No.1 ࡢ࢖ࢾࡢ 15 ᅇ┠ᢞ୚᫬ࡢ⾑₢୰⃰ᗘ᥎⛣࡟ྜ࠺ࡼ࠺࡟ㄪᩚࡋࡓࠋࡲࡓ㸪No.1 ࡢ࢖ࢾࡢ㧗⏝㔞࡟

࠾ࡅࡿ⾑₢୰⃰ᗘ᫬㛫᥎⛣ࢆ⾲⌧ࡍࡿࡓࡵ࡟㸪⬡⫫࡬ࡢ⃰ᗘ౫Ꮡⓗ࡞㣬࿴≉ᛶࢆࢩ࣑࣮ࣗࣞࢩࣙࣥ⏝

ࡢPfat (Pfat,sim) ࡟ᘧ 3-8 ࡢࡼ࠺࡟㏣ຍࡋࡓ᮲௳࡜㸪Pfatࡢ㣬࿴ࢆ௬ᐃࡋ࡞࠸᮲௳࡟࠾࠸࡚ࢩ࣑࣮ࣗࣞࢩࣙ ࣥࢆᐇ᪋ࡋࡓࠋ

, = , ,

ᘧ3-8

ࡇࡇ࡛Pf,maxࡣPfatࡢ᭱኱್㸪Pf,50ࡣPfat,simࡀ50%పୗࡍࡿ࡜ࡁࡢ TAK-357 ⾑₢୰⃰ᗘࢆ⾲ࡍࠋ ௒ᅇタᐃࡋࡓ඲࡚ࡢࣃ࣓࣮ࣛࢱ࡟ࡘ࠸࡚ኚ໬ࢆ⪃៖ࡋ࡞࠸ࢩ࣑࣮ࣗࣞࢩࣙࣥࢆࢥࣥࢺ࣮ࣟࣝ࡜⾲グࡍࡿࠋయ㔜పୗࢆ௬ᐃࡋࡓ≧ែኚ໬ࢆTable 3-1 ࡟♧ࡍࠋ⬡⫫⤌⧊࠾ࡼࡧ➽⫗ (PBPK ࣔࢹ࡛ࣝࡣṧ ⤌⧊࡜ࡋ࡚ㄝ᫂ࡋࡓ㒊ศ)㔜㔞ࡢపୗࡲࡓࡣ➽⫗㔜㔞ࡢࡳࡢపୗࡀ㸪No.2 ࡢ࢖ࢾ࡛ㄆࡵࡽࢀࡓయ㔜ప ୗ᫬࡛᭱ࡶྍ⬟ᛶࡢ㧗࠸ࢩࢼࣜ࢜࡜⪃࠼ࡽࢀࡓࠋࡑࡇ࡛ࢩࢼࣜ࢜1 ࡛ࡣ㸪᭱኱ࡢ⬡⫫㔜㔞పୗ࡜ࡋ࡚ 3 㐌㛫ࡢ㛫࡟ 90%ࡢ⬡⫫⤌⧊㔜㔞ࡀపୗࡋ㸪25%ࡢ➽⫗㔜㔞ࡀపୗࡋࡓሙྜࡢ TAK-357 ⾑₢୰⃰ᗘ ᥎⛣ࢆࢩ࣑࣮ࣗࣞࢺࡋࡓࠋ୍᪉࡛ࢩࢼࣜ࢜2 ࡛ࡣ㸪➽⫗ࡢࡳࡀ 58%㔜㔞పୗࢆ♧ࡋࡓሙྜࢆ௬ᐃࡋ ࡓࠋࡇࢀࡽࡢ2 ࡘࡢࢩࢼࣜ࢜࡟ຍ࠼࡚ࢡࣜ࢔ࣛࣥࢫ (ࢩࢼࣜ࢜ 3)㸪ᚰᢿฟ㔞 (ࢩࢼࣜ࢜ 4)㸪⬡⫫⤌⧊ /⾑ᾮศ㓄ಀᩘ (ࢩࢼࣜ࢜ 5)➼ࡑࡢ௚ࡢࣃ࣓࣮ࣛࢱኚ໬᫬ࡢឤᗘศᯒࡶ࠾ࡇ࡞ࡗࡓࠋࢩࢼࣜ࢜ 3 ࡛ࡣ CLintࡣࢥࣥࢺ࣮ࣟࣝࡢ10%࡟㸪ࢩࢼࣜ࢜ 4 ࡛ࡣᚰᢿฟ㔞ࡣࢥࣥࢺ࣮ࣟࣝࡢ 2 ಸ࡟య㔜పୗ㛤ጞ᫬Ⅼ ࡛༶᫬ኚ໬ࡉࡏࡓࠋࢩࢼࣜ࢜5࡛ࡣPfat,simࢆ3㐌㛫࠿ࡅ࡚య㔜పୗ㛤ጞ᫬Ⅼࡢ30%࡟ࡲ࡛పୗࡉࡏࡓࠋ

(29)

⤖⤖ᯝ 3.3 3.3.1 ື≀ᐇ㦂 TAK-357ࢆ1000 mg/kgࡢ⏝㔞࡛࢖ࢾ2༉࡬15᪥㛫཯᚟ᢞ୚ᚋࡢ⾑₢୰⃰ᗘ᥎⛣ࢆFig. 3-2࡟♧ࡍࠋ 2 㢌ࡢ࢖ࢾࡣඹ࡟཯᚟ᢞ୚࡟ࡼࡾ⾑₢୰⃰ᗘࡀୖ᪼ࡋࡓࠋ2 㢌ࡢ࠺ࡕ᭱⤊ᢞ୚ 2 㐌㛫ᚋ࡟⾑₢୰⃰ᗘ ࡀୖ᪼ࡋࡓNo.2ࡢ࢖ࢾࡣయ㔜ࡀ12.2 kg (᭱⤊ᢞ୚1㐌㛫ᚋ) ࠿ࡽ9.4 kg (᭱⤊ᢞ୚4㐌㛫ᚋ) ࡲ࡛23% పୗࡋࡓ (Fig. 3-3)ࠋࡇࡢ No.2 ࡢ࢖ࢾࡢ๗᳨᫬ࡢᚰ⮚㸪⫵㸪⫢⮚ࡢ⤌⧊㔜㔞ࡣࡑࢀࡒࢀ 126.0㸪80.4 ࠾ࡼࡧ372.8 g ࡛࠶ࡾ㸪፹యᢞ୚ࡢࢥࣥࢺ࣮ࣟࣝ⩌ࡢ⤌⧊㔜㔞 81.8㸪63.7 ࠾ࡼࡧ࡜ 201.9g ࡜ẚ㍑ࡋ࡚ 㔜࠿ࡗࡓࠋ 3.3.2 PBPK ࣔࢹࣜࣥࢢ PBPK ࣔࢹࣝࡣPK 㐣⛬࡟㔜せ࡞᭱ᑠᩘࡢࢥࣥࣃ࣮ࢺ࣓ࣥࢺ࡛ࢹ࣮ࢱࢆ㐺ษ࡟⾲⌧࡛ࡁࡿࣔࢹࣝࢆ ᵓ⠏ࡋࡓࠋ᭱⤊ࡢPBPK ࣔࢹࣝࡣ⾑ᾮ㸪⫢⮚㸪⬡⫫⤌⧊㸪⓶⭵࠾ࡼࡧṧ⤌⧊ࢥࣥࣃ࣮ࢺ࣓ࣥࢺ࡛ᵓ ᡂࡉࢀ࡚࠸ࡿ (Fig. 3-1)ࠋ⏕⌮Ꮫⓗࣃ࣓࣮ࣛࢱ࠾ࡼࡧ⸆≀≉␗ⓗࣃ࣓࣮ࣛࢱࢆ Table 3-2 ࡟♧ࡍࠋ඲࡚ ࡢࣃ࣓࣮ࣛࢱࡣ┦ᑐᶆ‽ㄗᕪࡀᑠࡉࡃṇ☜࡟᥎ᐃࡉࢀࡓࠋయ㔜⿵ṇࢆࡋࡓCLint (L/h/kg) ࡣ࢖ࢾ࡟࠾ ࠸࡚ࣛࢵࢺࡼࡾప࠿ࡗࡓࠋWell-stirred ࣔࢹࣝࢆ⏝࠸࡚⟬ฟࡋࡓ࢖ࢾࡢ⫢ࢡࣜ࢔ࣛࣥࢫࡣ 25 mL/h/kg ࡛࠶ࡾ㸪➨2 ❶࡛ࣀࣥࢥࣥࣃ࣮ࢺ࣓ࣥࢺࣔࢹࣝゎᯒ࡛⟬ฟࡋࡓ್ (24 mL/h/kg) ࡜ྠ➼࡛࠶ࡗࡓࠋࣇ ࢕ࢵࢸ࢕ࣥࢢ⤖ᯝࡣFig. 3-4 ࡟♧ࡍࠋᵓ⠏ࡋࡓ᭱ᑠࡢ PBPK ࣔࢹࣝࡣヨ㦂⏝㔞⠊ᅖ࡟࠾ࡅࡿࣛࢵࢺ࠾ ࡼࡧ࢖ࢾࡢPK ࢹ࣮ࢱࢆ㐺ษ࡟グ㏙ࡋࡓࠋ 3.3.3 ࢩ࣑࣮ࣗࣞࢩࣙࣥ No.1ࡢ࢖ࢾࡢ⾑₢୰⃰ᗘ᫬㛫᥎⛣ࡣ㧗⏝㔞࡟ㄪᩚࡋࡓPBPKࣔࢹ࡛ࣝ㐺ษ࡟ࢩ࣑࣮ࣗࣞࢺ࡛ࡁࡓࠋ Ka ࠾ࡼࡧ F ࡣࡑࢀࡒࢀ 0.1 ࠾ࡼࡧ 0.027 ࡟タᐃࡋࡓࠋPfatࡢ㣬࿴ࢆ௬ᐃࡋࡓࢩ࣑࣮ࣗࣞࢩࣙࣥ࡟࠾࠸ ࡚ࡣPf,maxࡣPBPK ࣔࢹࣜࣥࢢࡢ⤖ᯝ࠿ࡽ 495 ࡟タᐃࡋ㸪Pf,50ࡣ10 g/mL ࡜ࡋࡓࠋ᪉ἲࡢ㡯࡟グ㍕ࡋ ࡓࡼ࠺࡟⤌⧊㔜㔞ኚ໬ࡢ2 ࡘࡢ௬ᐃࡢࡶ࡜ࢩ࣑࣮ࣗࣞࢩࣙࣥࢆ⾜ࡗࡓࠋࡑࢀࡣㄆࡵࡽࢀࡓయ㔜ኚ໬᫬

(30)

࡟᭱ࡶྍ⬟ᛶࡢ࠶ࡿせᅉ࡜ࡋ࡚⬡⫫⤌⧊࠾ࡼࡧ➽⫗㔜㔞ࡀపୗࡋࡓ᮲௳ (ࢩࢼࣜ࢜ 1) ࠾ࡼࡧ➽⫗㔜㔞ࡢࡳࡀపୗࡋࡓ᮲௳ (ࢩࢼࣜ࢜ 2) ࡛࠶ࡿࠋࢩࢼࣜ࢜ 1 ࡟࠾࠸࡚ࡣ 90%ࡢ⬡⫫⤌⧊࡜ 25%ࡢṧ⤌⧊ ᐜ✚ࡀ3 㐌㛫࠿ࡅ࡚పୗࡋࡓ᮲௳࡟࡚ࢩ࣑࣮ࣗࣞࢺࡋࡓ (Fig 3-5)ࠋࡑࡢ⤖ᯝ㸪ᐇ㝿࡟ㄆࡵࡽࢀࡓ TAK-357 ࡢ⾑₢୰⃰ᗘࢆࢩ࣑࣮ࣗࣞࢺࡍࡿࡇ࡜࡟ᡂຌࡋࡓ (Fig .3-6)ࠋ୍᪉࡛➽⫗⤌⧊ࡢࡳࡀపୗࡋ ࡓ࡜௬ᐃࡋࡓࢩࢼࣜ࢜2 ࡛ࡣ No.2 ࡢ࢖ࢾࡢ⾑₢୰⃰ᗘ᥎⛣ࢆ෌⌧ࡍࡿࡇ࡜ࡣ࡛ࡁ࡞࠿ࡗࡓ (ࢥࣥࢺ ࣮ࣟࣝࢩ࣑࣮ࣗࣞࢩࣙࣥࡢ⤖ᯝ࡜୍⮴ࡍࡿࡓࡵ࡟Fig .3-6 ࡟ࡣᮍグ㍕)ࠋCLintࡢపୗ (ࢩࢼࣜ࢜ 3) ࡣ ࢥࣥࢺ࣮ࣟࣝࢩ࣑࣮ࣗࣞࢩࣙࣥ࡜ẚ㍑ࡋ࡚ⱝᖸ㧗࠸ࡢࡳ࡛࠶ࡗࡓࠋᚰᢿฟ㔞ኚ໬ (ࢩࢼࣜ࢜ 4) ࡣࢥ ࣥࢺ࣮ࣟࣝࢩ࣑࣮ࣗࣞࢩࣙࣥ࡜࡯ࡰ୍⮴ࡋࡓ(Fig .3-6 ࡟ࡣᮍグ㍕)ࠋ⬡⫫⤌⧊/⾑ᾮศ㓄ಀᩘ (Pfat,sim) ࡢ పୗ (ࢩࢼࣜ࢜ 5) ࡣ TAK-357 ࡢ⾑₢୰⃰ᗘࢆୖ᪼ࡉࡏࡓࠋ ⪃⪃ᐹ 3.4 2 㐌㛫཯᚟ᢞ୚Ᏻ඲ᛶヨ㦂࡟࠾࠸࡚㸪ᛴ⃭࡞య㔜పୗ࡜ඹ࡟␗ᖖ࡞ TAK-357 ⾑₢୰⃰ᗘࡢୖ᪼ࡀ ㄆࡵࡽࢀࡓ (Figs. 3-2 ࠾ࡼࡧ 3-3)ࠋ⾑₢୰⃰ᗘࡢ஧ᓠᛶࡣ㏻ᖖ㸪⭠⫢ᚠ⎔ཪࡣ୙㐃⥆࡞྾཰㒊఩ࡀᙳ 㡪ࡍࡿሙྜ࡟ㄆࡵࡽࢀࡿࠋ୍᪉࡛㸪ᮏヨ㦂࡟࠾ࡅࡿ⾑₢୰⃰ᗘୖ᪼ࡣ᭱⤊ᢞ୚ᚋࡢ࠿࡞ࡾ㐜࠸ᾘኻ┦ ࡟ㄆࡵࡽࢀࡓࠋ⭠⫢ᚠ⎔ࡸ㐜࠸྾཰㒊఩࡟ࡼࡿᙳ㡪ࡣࠕ᫬㛫ࠖ࠿ࡽࠕ᪥ࠖࡢ᫬㛫༢఩࡛ㄆࡵࡽࢀࡿࡓ ࡵ㸪ᮏヨ㦂࡛ㄆࡵࡽࢀࡓ⾑₢୰⃰ᗘୖ᪼ࡢࠕ㐌ࠖࡢ᫬㛫༢఩࡜ࡣ኱ࡁࡃ␗࡞ࡿࠋࡑࡢࡓࡵ㸪ࡇࢀࡽࡢ ⭠⫢ᚠ⎔➼ࡣ௒ᅇࡢ⌧㇟ࡢ࣓࢝ࢽࢬ࣒࡜ࡣ⪃࠼࡟ࡃ࠸ࠋࡶ࠺୍ࡘࡢྍ⬟ᛶࡢ࠶ࡿせᅉࡣ⬡⫫⤌⧊ᐜ✚ ࡢῶᑡ࡟ࡼࡿ⬡⫫⤌⧊୰ࡢTAK-357 ࡢ⾑₢୰࡬ࡢ෌ศᕸ࡛࠶ࡿࠋᩥ⊩ሗ࿌࡛ࡣ㧗⬡⁐ᛶ≀㉁ࡢ PK ࡣయ⤌ᡂ࡟ࡼࡗ࡚ᙳ㡪ࡉࢀ㸪㣚㣹࡟ࡼࡾ⾑₢୰⃰ᗘࡀୖ᪼ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ (37, 64, 65)ࠋ⬡ ⫫⤌⧊୰TAK-357 ⃰ᗘࡣ⫢⮚㸪⭈⮚㸪⫵➼௚ࡢ⤌⧊୰⃰ᗘ࡜ẚ㍑ࡋ࡚࠿࡞ࡾ㧗ࡃ㸪ࣛࢵࢺࡸ࢖ࢾ࡟ ࠾࠸࡚⬡⫫⤌⧊ࡀTAK-357 ࡢ㈓ⶶᗜ࡜ࡋ࡚ാ࠸࡚࠸ࡿࡓࡵ (27)㸪⬡⫫⤌⧊࠿ࡽ⾑₢୰࡬ࡢ෌ศᕸࡀ ␗ᖖ࡞⾑₢୰⃰ᗘୖ᪼࡟㛵ࢃࡗ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋᮏ◊✲࡛ࡣ␗ᖖ࡞⾑₢୰⃰ᗘୖ᪼ࡀ⬡⫫ ⤌⧊㔜㔞⌧㇟࡛ㄝ࡛᫂ࡁࡿ࠿ྰ࠿ࢆ⌧Ꮡࢹ࣮ࢱࢆ⏝࠸ࡓPBPK ゎᯒ᳨࡛ドࡋࡓࠋPBPK ࣔࢹࣝゎᯒࡣ

(31)

࠶ࡿ≉ᐃࡢ⤌⧊ࡢ⸆≀⃰ᗘࢆᐃ㔞ⓗ࡟ண ྍ⬟࡛࠶ࡾ㸪ࡑࢀࡣ⬡⫫⤌⧊㔜㔞ኚ໬ࡢPK ࡟୚࠼ࡿᙳ㡪 ࢆホ౯ࡍࡿࡢ࡟᭷⏝࡛࠶ࡿࠋ PBPK ࣔࢹࣝࡢᵓ⠏ࡣᡂຌࡋ㸪ࣃ࣓࣮ࣛࢱ್ࡀ᥎ᐃࡉࢀࡓ (Table 3-2, Fig 3-3)ࠋ᥎ᐃࡉࢀࡓ㠀ᖖ࡟ 㧗࠸⬡⫫⤌⧊/⾑୰ศ㓄ಀᩘࡣ㸪௨๓࡟ሗ࿌ࡉࢀ࡚࠸ࡿ㧗࠸⬡⁐ᛶ࡜⬡⫫⤌⧊/⾑୰ศ㓄ಀᩘࡢ㛵ಀᛶ ࡜▩┪ࡢ࡞࠸ࡶࡢ࡛࠶ࡗࡓ (22, 56)ࠋࡇࡢ㧗࠸ศ㓄ಀᩘࡣ TAK-357 ࡀ㠀ᖖ࡟㛗ࡃ⬡⫫⤌⧊୰࡟ṧᏑࡍ ࡿཎᅉ࡜⪃࠼ࡽࢀࡿࠋNo.2 ࡢ࢖ࢾࡢ᭱⤊᫬Ⅼ࡟࠾ࡅࡿ୺せ⮚ჾ (⬻㸪ᚰ⮚㸪⫵㸪⫢⮚㸪⭈⮚࠾ࡼࡧ⭁ ⮚) 㔜㔞ࡣࢥࣥࢺ࣮ࣟࣝࡢ࢖ࢾ࡜ྠ➼ࡶࡋࡃࡣ㔜࠿ࡗࡓࡓࡵ㸪య㔜పୗࡢ୺࡞せ⣲ࡣ⬡⫫⤌⧊࠾ࡼࡧ ➽⫗㔜㔞ࡢపୗ࡟ࡼࡿࡶࡢ࡛࠶ࡿ࡜௬ᐃࡋࡓࠋయ㔜పୗࡢᙳ㡪ࢆࢩ࣑࣮ࣗࣞࢺࡍࡿ๓࡟㸪య㔜పୗࡢ ㄆࡵࡽࢀ࡞࠿ࡗࡓNo.1 ࡢ࢖ࢾࡢ⾑₢୰⃰ᗘ᥎⛣ࢆ㐺ษ࡟グ㏙ࡍࡿࡼ࠺࡟㸪F,Ka࠾ࡼࡧPfatࡢࣃ࣓࣮ࣛ ࢱ್ࢆ᭱㐺໬ࡋࡓࠋTAK-357 ࡢ⁐ゎᗘࡣప࠸ࡓࡵ㧗⏝㔞࡟࠾ࡅࡿ⾑₢୰ᭀ㟢㔞ࡣ⏝㔞ẚ௨ୗࡢୖ᪼ ࢆ♧ࡋ㸪྾཰ࡶ㐜ࡃ࡞ࡿࡇ࡜ࡀ᝿ᐃࡉࢀࡿࠋࡑࡢࡓࡵ㸪F ࡸ Kaࡣప⏝㔞࡛᥎ᐃࡉࢀࡓ್ࡼࡾࡶప࠸ ್ࢆタᐃࡋࡓࠋF ࡸ Kaࡢ᭱㐺໬ᚋࡶ᭱⤊ᢞ୚ᚋࡢ⾑₢୰⃰ᗘ᫬㛫᥎⛣ࡢண ್࡜ᐇ ್ࡢ㛫࡟ࡣⱝ ᖸࡢゎ㞳ࡀṧࡗࡓࠋࡇࡢゎ㞳ࢆゎᾘࡍࡿࡓࡵ࡟TAK-357 ࡢ⬡⫫⤌⧊࡬ࡢ⛣⾜ (Pfat,sim) ࡢ㣬࿴࡟ࡘ࠸ ࡚ࡶ⪃៖ࡋࡓࠋࣔࢹࣝ࠿ࡽ᥎ᐃࡋࡓTAK-357 ࡢ⬡⫫⤌⧊୰⃰ᗘࡣ㠀ᖖ࡟㧗࠿ࡗࡓࡓࡵ (1000 g/g ௨ ୖ)㸪㣬࿴ࡢྍ⬟ᛶࡣ༑ศ࠶ࡿ࡜⪃࠼ࡽࢀࡓࠋ୍᪉࡛㸪ࡑࡢ௚ࡢࣃ࣓࣮ࣛࢱ(CLint➼)࡟୚࠼ࡓኚ໬࡛ࡣ ᐇ ್ࡢ⃰ᗘ᥎⛣ࢆグ㏙ࡍࡿࡢ࡟᭷ຠ࡛ࡣ࡞࠿ࡗࡓࠋࡇࢀࡽࡢ᭱㐺໬ࡋࡓࣃ࣓࣮ࣛࢱࢆ⏝࠸ࡓ᮲௳࠾ ࡼࡧPfat,simࡢ㣬࿴ࢆ௬ᐃࡋ࡞࠸᮲௳࡛య㔜పୗࡢᙳ㡪ࢆホ౯ࡋࡓࠋ⬡⫫⤌⧊࠾ࡼࡧ➽⫗㔜㔞ኚ໬ࡢ๻ ⓗ࡞ኚ໬౛ࢆ௬ᐃࡋ࡚ (Fig. 3-5)㸪TAK-357 ࡢ⾑₢୰⃰ᗘࢆࢩ࣑࣮ࣗࣞࢺࡋࡓ⤖ᯝ㸪ᐇ ್࡜ྠᵝࡢ ⾑₢୰⃰ᗘୖ᪼ࢆࢩ࣑࣮ࣗࣞࢺࢆࡍࡿࡇ࡜ࡀ࡛ࡁࡓ (Fig. 3-6㸪ࢩࢼࣜ࢜ 1)ࠋ୍᪉࡛➽⫗㔜㔞ࡢࡳࢆప ୗࡉࡏࡓሙྜ࡟ࡣ⸆≀⃰ᗘࡢୖ᪼ࡣㄆࡵࡽࢀ࡞࠿ࡗࡓ (ࢩࢼࣜ࢜ 2)ࠋࡇࡢഴྥࡣ Pfat,simࡢ㣬࿴ࢆ௬ᐃ ࡋ࡚ࡶࡋ࡞ࡃ࡚ࡶྠᵝ࡛࠶ࡗࡓࠋࡇࢀࡽࡢࢩ࣑࣮ࣗࣞࢩࣙࣥࡣTAK-357 ࡢ⾑₢୰⃰ᗘࡀ⬡⫫⤌⧊㔜㔞ࡢኚ໬࡟ᑐࡋ࡚ࡣᙳ㡪ࢆཷࡅࡿࡀ㸪➽⫗㔜㔞ࡢኚ໬࡟ᑐࡋ࡚ࡣᙳ㡪ࢆཷࡅ࡞࠸ࡇ࡜ࢆ♧ࡋ࡚࠸ࡿࠋ No.2 ࡢ࢖ࢾࡣ᪥࿴ぢឤᰁ⑕ࡢᙳ㡪࡛␗ᖖ࡞⏕⌮Ꮫⓗ࡞≧ែ࡛࠶ࡗࡓࡓࡵ㸪య㔜ࡸ⤌⧊㔜㔞௨እࡢせ ⣲ࡶኚ໬ࡋ࡚࠸ࡓྍ⬟ᛶࡣྰᐃ࡛ࡁ࡞࠸ࠋࡋ࠿ࡋ࡞ࡀࡽ㸪ᚰᢿฟ㔞㸪௦ㅰάᛶ (CLint)㸪⬡⫫⤌⧊࡬ࡢ

(32)

⛣⾜ẚ⋡ (Pfat) ࡞࡝ࡢኚ໬ࢆホ౯࡛ࡁࡿᐇ㦂ࢹ࣮ࢱࡣ࡞࠿ࡗࡓࠋࡑࡇ࡛ࡇࢀࡽࡢせ⣲ࡢ TAK-357 ࡢ ⾑₢୰⃰ᗘ᥎⛣࡟୚࠼ࡿᙳ㡪ࢆホ౯ࡍࡿࡓࡵ࡟ឤᗘศᯒࢆ⾜ࡗࡓ (ࢩࢼࣜ࢜ 3-5)ࠋCLintࡢపୗࢆ௬ᐃ ࡋࡓࢩࢼࣜ࢜3 ࡛ࡣᾘኻࡀ㠀ᖖ࡟㐜ࡃ࡞ࡿࡶࡢࡢ㸪⃰ᗘୖ᪼ࡣࢩ࣑࣮ࣗࣞࢺࡉࢀ࡞࠿ࡗࡓࠋᚰᢿฟ㔞 ኚ໬᫬ࡣࢥࣥࢺ࣮ࣟࣝࡢ⾑₢୰⃰ᗘ᥎⛣࡜୍⮴ࡋࡓ (ࢩࢼࣜ࢜ 4)ࠋPfatࡢపୗࢆ௬ᐃࡋࡓࢩࢼࣜ࢜5 ࡟࠾࠸࡚ࡣ⾑₢୰⃰ᗘࡀୖ᪼ࡋࡓࠋࢩࢼࣜ࢜1 ࠾ࡼࡧࢩࢼࣜ࢜ 5 ࡣ࡝ࡕࡽࡶ⬡⫫⤌⧊୰ࡢ TAK-357 ࡀ⾑₢୰࡬࡜ᨺฟࡉࢀ࡚࠸ࡿࡇ࡜ࢆ⾲ࡋ࡚࠸ࡿࠋ௨ୖࡢࡇ࡜࠿ࡽ㸪࢖ࢾTK ヨ㦂࡛ㄆࡵࡽࢀࡓ TAK-357 ࡢ␗ᖖ࡞⾑₢୰⃰ᗘୖ᪼ࡀ୺࡟య㔜పୗ࡟㉳ᅉࡋࡓ⬡⫫⤌⧊୰࠿ࡽ⾑₢୰࡬ࡢ෌ศᕸ࡛ㄝ ᫂ྍ⬟࡛࠶ࡿࡇ࡜ࡀ♧၀ࡉࢀࡓࠋࡋࡓࡀࡗ࡚㸪TAK-357 ௨እࡢ㧗⬡⁐ᛶ⸆≀ࡢ PK ࡶ▷ᮇ㛫ࡢ⬡⫫⤌ ⧊㔜㔞పୗ࡟ࡼࡗ࡚ᙳ㡪ࢆཷࡅࡿࡇ࡜ࡶ⪃࠼ࡽࢀࡿࠋ ௒ᅇࡢPBPK ࣔࢹࣝ࠿ࡽࡢࢩ࣑࣮ࣗࣞࢩ࡛ࣙࣥࡣ㸪⾑₢࡜⬡⫫⤌⧊௨እࡢ⤌⧊࡟࠾ࡅࡿ TAK-357 ⃰ᗘࡀ⾑₢୰⃰ᗘୖ᪼ࡢ2 ḟⓗ࡞ᙳ㡪࡜ࡋ࡚ୖ᪼ࡍࡿࡇ࡜ࡀண ࡉࢀࡿࠋࡶࡋ㸪TAK-357 ࡢࡳ࡞ࡽ ࡎࡑࡢ௚ࡢ㧗⬡⁐ᛶ⸆≀ࡢ⮫ᗋ἞⒪୰࡟ᛴ⃭࡞య㔜పୗࡀ㉳ࡁࡓ㝿࡟ࡣ㸪⾑₢୰ࡸᶆⓗ⤌⧊୰ࡢ⃰ᗘ ୖ᪼ࡀ㉳ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡿࠋࡉࡽ࡟㸪ࡇࢀࡽࡢ⸆≀ࡢ἞⒪⃰ᗘᇦࡀ⊃࠸ሙྜ㸪ᛴ࡞⃰ᗘୖ᪼࡟ࡼ ࡾᏳ඲ᛶୖࡢၥ㢟ࡀⓎ⏕ࡍࡿྍ⬟ᛶࡶ࠶ࡿࠋGeyer ࡽࡣ⬡⫫⤌⧊ࡀ⾑୰⃰ᗘࢆపୗࡉࡏࡿࡇ࡜࡟ࡼࡾ㸪 ẘ≀࠿ࡽឤཷᛶࡢ㧗࠸⤌⧊ࢆᏲࡿᙺ๭ࢆᢸࡗ࡚࠸ࡿ࡜♧၀ࡋ࡚࠸ࡿ (26)ࠋࡼࡗ࡚㸪⬡⫫㔜㔞ࡀቑຍ ࡉࡏࡿࡇ࡜࡟ࡼࡾ㸪㧗⬡⁐ᛶ⸆≀ࡢ⾑₢୰⃰ᗘࡀపୗࡋ㸪⸆≀ࡢᏳ඲ᛶࢆ㧗ࡵࡿࡇ࡜ࡀྍ⬟࠿ࡶࡋࢀ ࡞࠸ࠋࡋ࠿ࡋ࡞ࡀࡽ୍᪉࡛㸪ࣄࢺࡸື≀࡛⬡⫫⤌⧊ࡀከ࠸ሙྜ࡟ࡣ⸆≀ࡢయෆ࠿ࡽࡢ⥲᤼ἥࡣ㐜ࡃ࡞ ࡿ࡜⪃࠼ࡽࢀࡿࠋࡇࢀࡣయ㔜ኚ໬࡟㉳ᅉࡍࡿᏳ඲ᛶࡸ⸆⌮ຠᯝࡢኚ໬ࢆホ౯ࡍࡿୖ࡛㔜せ࡞࣏࢖ࣥࢺ ࡛࠶ࡿࠋ௨ୖࡢࡇ࡜࠿ࡽ㸪㠀ᖖ࡟㧗⬡⁐ᛶࡢ⸆≀ࡢᏳ඲ᛶホ౯࡟ࡣ㸪༢⣧࡟⾑ᾮ୰⃰ᗘࡢపୗ࡛Ᏻ඲ ᛶࡀ☜ಖࡉࢀࡿ࡜࠸࠺⪃࠼ࢆᥦ᱌ࡍࡿࡢࡳ࡛࡞ࡃ㸪⤌⧊ศᕸ࡜࠸࠺ほⅬ࠿ࡽ⾑୰⃰ᗘపୗ࡟కࡗ୍࡚ 㒊ࡢ⤌⧊ෆ⃰ᗘࡣ㧗ࡃ࡞ࡿྍ⬟ᛶࡶ࠶ࡿࡇ࡜࠿ࡽ㸪ࡑࡢ⸆≀࡟ᅛ᭷ࡢADME ≉ᛶࢆ⇍▱ࡋࡓᰂ㌾࠿ ࡘ㐺ษ࡞⸆≀⃰ᗘኚື࡬ࡢ⪃ᐹࡀᚲせ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡓࠋ

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ᑠᑠᣓ 3.5

ᮏ❶ࡢゎᯒ࡛ࡣ㸪㠀ᖖ࡟㧗⬡⁐ᛶ࡛⬡⫫⤌⧊࡬㧗⃰ᗘศᕸࡍࡿ⸆≀ࡢPK ࡣ⬡⫫⤌⧊㔜㔞ࡢᛴ⃭࡞

(34)

㧗⃰ᗘ⬡⫫࡬ศᕸࡍࡿ⸆≀ࡢືែ࡟୚࠼ࡿయ⬡⫫ኚ໬ࡢᙳ㡪

➨

4❶

ࡣࡌࡵ࡟ 4.1 ⤌⧊ศᕸࡣ⸆≀ࡢືែ࡟ᐤ୚ࡍࡿ㔜せ࡞㐣⛬ࡢ୍ࡘ࡛࠶ࡿࠋ⸆≀ࡢศᕸࡣ୺࡟⬡⁐ᛶ㸪pKa㸪⸆≀ ≉␗ⓗ࡞⺮ⓑ㉁ࡸࡑࡢ௚ᡂศ࡬ࡢ⤖ྜ࡞࡝࡟ࡼࡗ࡚≉ᚩ௜ࡅࡽࢀࡿ (30, 51)ࠋࡑࡋ࡚㸪⤌⧊ศᕸࡢ⛬ ᗘࡣ⤖ᯝ࡜ࡋ࡚⾑₢୰⃰ᗘࡸࡑࡢ༙ῶᮇ㸪యෆ࡟࠾ࡅࡿṧᏑ㸪⥲᤼ἥ㏿ᗘ࡞࡝࡟ᙳ㡪ࡍࡿࠋ๓❶ࡲ࡛ ࡟ሗ࿌ࡋࡓࡼ࠺࡟㸪⎔ቃẘ≀࡛࠶ࡿPCB ࡸ PCDD ࡣ⬡⫫⤌⧊࡟⵳✚ࡋ㸪⬡⫫⤌⧊ࡢ㔜㔞ኚ໬࡟ࡼࡿ ࡑࡢືែࡀᙳ㡪ࢆཷࡅ㸪⬡⫫⤌⧊࠿ࡽ⾑₢୰࡬෌ศᕸࡋ㸪᤼ἥࡀຍ㏿ࡉࢀࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ (34, 37, 64, 65)ࠋࡶࡋ㸪⸆≀⃰ᗘࡀయ㔜㸪య⤌ᡂ (body mass index ➼) ࡸ㝖⬡⫫㔜㔞➼࡟ࡼࡗ࡚ኚ໬ࡍ ࡿࡢ࡛࠶ࢀࡤ㸪⸆⌮స⏝ࡸᏳ඲ᛶ≉ᛶࡀኚ໬ࡍࡿྍ⬟ᛶࡀ࠶ࡿࠋ⮫ᗋ࡛౑⏝ࡉࢀ࡚࠸ࡿ࠸ࡃࡘ࠿ࡢ⸆ ≀࡟࠾࠸࡚ࡣ㸪య㔜࠾ࡼࡧయ⤌ᡂ࡟ࡼࡿᢞ୚㔞ㄪᩚࡀ᥎ዡࡉࢀ࡚࠸ࡿ (12, 23)ࠋ⫧‶≧ែ࡟࠾ࡅࡿ⸆ ≀ືែ࡟ࡘ࠸࡚ࡣ᭱㏆ࡢ⥲ㄝ࡟ࡲ࡜ࡵࡽࢀ࡚࠸ࡿࡶࡢࡢ (41)㸪⬡⫫⤌⧊࡬㧗⃰ᗘศᕸࡍࡿ⸆≀࡜⫧ ‶࡜ࡢ㛵ಀ࡟ࡘ࠸࡚ࡢሗ࿌ࡣᑡ࡞࠸ࠋᮏ❶࡛ࡣయ⤌ᡂࡢ㐪࠸ࡲࡓࡣయ⤌ᡂࡢኚ໬ࡀ㧗⬡⁐ᛶ⸆≀ࡢయ ෆືែ࡟୚࠼ࡿᙳ㡪ࢆTAK-357 ࢆ௦⾲⸆≀࡜ࡋ࡚⏝࠸࡚ホ౯ࡋࡓࠋ➨ 3 ❶࡟࠾࠸࡚ TAK-357 ࡣᛴ⃭ ࡞⬡⫫㔜㔞ኚ໬࡟ࡼࡗ࡚⾑₢୰⃰ᗘࡀኚືࡍࡿࡇ࡜ࢆ♧ࡋࡓࠋࡋ࠿ࡋ࡞ࡀࡽ㸪ࡇࢀࡽࡢᛴ⃭࡞య㔜ኚ ໬ࡀ⮫ᗋ࡛㉳ࡁࡿྍ⬟ᛶࡣప࠸ࠋ⮫ᗋ࡟࠾࠸࡚ࡣ㸪཯᚟ᢞ୚ᮇ㛫୰ࡢᐃᖖ≧ែ࡟࠾࠸࡚ẚ㍑ⓗ⦆ࡸ࠿ ࡞య㔜ኚ໬ࡀ㉳ࡾࡸࡍ࠸ࢩࢼࣜ࢜࡜⪃࠼ࡽࢀࡿࠋᮏ◊✲࡛⫧‶ື≀࡜ṇᖖື≀࡟࠾ࡅࡿTAK-357 ࡢ యෆືែࢆẚ㍑ࡋࡓ࠺࠼㸪㧗⬡⁐ᛶ⸆≀ࡢయෆືែ࡟୚࠼ࡿయ⤌ᡂࡢ⦆ࡸ࠿࡞య㔜ኚ໬ࡀ୚࠼ࡿᙳ㡪 ࢆPBPK ࣔࢹࣝゎᯒ࡛ホ౯ࡋࡓࠋ ᐇ㦂ᮦᩱ࡜᪉ἲ 4.2 4.2.1 ⿕㦂≀㉁㸪ヨ⸆ TAK-357 (ྵ㔞:100%) ࡣṊ⏣⸆ရᕤᴗᰴᘧ఍♫㸪〇⸆◊✲ᡤ࡛ྜᡂࡉࢀࡓࡶࡢࢆ⏝࠸ࡓࠋ [14_{C]TAK-357 (ᨺᑕ⛉Ꮫⓗ⣧ᗘ>97%) ࡣࣅ࢜ࣈࣜࢵࢪᰴᘧ఍♫࡛ྜᡂࡉࢀࡓࡶࡢࢆ⏝࠸ࡓࠋࡑࡢ௚ࡢ} ヨ⸆࡜ヨᾮࡣ࿴ග⣧⸆ᕤᴗᰴᘧ఍♫ࡶࡋࡃࡣPerkin Elmer ࡼࡾධᡭࡋࡓࠋ

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4.2.2 ື≀

౑⏝ࡋࡓ⫧‶ᆺ⢾ᒀ⑓ࣔࢹࣝࣛࢵࢺ࡛࠶ࡿWistar fatty ࣛࢵࢺ࠾ࡼࡧࡑࡢᑐ↷ື≀ Wistar lean ࣛࢵ

ࢺࡣṊ⏣ࣛࣅࢵࢡࢫ (኱㜰) ࡼࡾ㉎ධࡋࡓࠋࣛࢵࢺࡣ㞝ᛶ࡛ᢞ୚㛤ጞ᫬ 16 㐌㱋࡛ 1 ⩌ 4 ༉࡛౑⏝ࡋ

ࡓࠋ඲࡚ࡢື≀ࡣࢫࢸࣥࣞࢫࢣ࣮ࢪ࡛㣫⫱ࡋ㸪㣧Ỉ࠾ࡼࡧ㣗㣵࡜ࡋ࡚ࡢCR-LPF ࡣ⮬⏤ᦤྲྀ࡜ࡋࡓࠋ

4.2.3 ື≀ᐇ㦂

[14_{C]TAK-357 ࡣࢪ࣓ࢳࣝ࢔ࢭࢺ࢔࣑ࢻ:1,3-ࣈࢱࣥࢪ࣮࢜ࣝࡢ 1:1 ࡢΰᾮ࡟⁐ゎࡋ㸪Wistar fatty ࣛࢵ}

ࢺ࠾ࡼࡧWistar lean ࣛࢵࢺ࡟㟼⬦ෆᢞ୚ࡋࡓࠋࣛࢵࢺࡣᒀࡸ⣅ࢆᅇ཰ࡍࡿࡓࡵ࡟ 7 ᪥㛫௦ㅰࢣ࣮ࢪෆ

࡛㣫⫱ࡋࡓࠋᢞ୚7 ᪥ᚋ࠿ࡽ 30 ᪥ᚋࡲ࡛ࡣ㣫⫱ࢣ࣮ࢪෆ࡛㣫⫱ࡋ㸪⣅ࢆ 1 㐌㛫࡟ 2 ᅇᅇ཰ࡋࡓࠋ⾑

ᾮヨᩱࡣᢞ୚ᚋ5, 15, 30 ศ, 1, 4, 8, 24 ᫬㛫, 2, 4, 8, 11, 15, 18, 21, 24, 28 ࠾ࡼࡧ30 ᪥ᚋ࡟ᑿ㟼⬦࠿ࡽ᥇ྲྀ

ࡋࡓࠋᢞ୚30 ᪥ᚋ࡟ࣛࢵࢺࢆ࢖ࢯࣇࣝࣛࣥࢆ⏝࠸ࡓ㯞㓉ୗ࡟࠾࠸࡚ᨺ⾑⮴Ṛࡉࡏ㸪ⓑⰍ⬡⫫⤌⧊࠾

ࡼࡧ〓Ⰽ⬡⫫⤌⧊ࢆ᥇ྲྀࡋࡓࠋ

TAK-357 ࡣ 0.5%࣓ࢳࣝࢭ࣮ࣝࣟࢫỈ⁐ᾮ࡟ᠱ⃮ࡋ㸪Wistar fatty ࣛࢵࢺ࠾ࡼࡧ Wistar lean ࣛࢵࢺ࡟ ༢ᅇࡶࡋࡃࡣ1 ᪥ 1 ᅇ཯᚟⤒ཱྀᢞ୚ࢆࡋࡓࠋ༢ᅇᢞ୚⩌࡛ࡣᢞ୚ᚋ 0.5, 1, 2, 4, 8, 24 ᫬㛫, 2, 4, 8, 11, 15, 18, 21, 24, 28 ࠾ࡼࡧ 31 ᪥ᚋ࡟᥇⾑ࡋࡓࠋ཯᚟ᢞ୚⩌ࡣ Day 0 (ึᅇᢞ୚᪥)㸪Day 13 ࠾ࡼࡧ Day 17 ࡛ ࡣᢞ୚ᚋ0.5, 1, 2, 4, 8 ࠾ࡼࡧ24 ᫬㛫࡟᥇⾑ࡋ㸪Day 6, 9, 13, 19, 22, 27 ࡟ࡣᢞ୚๓࡟1 ᅇࡢࡳ᥇⾑ࡋࡓࠋ

⾑₢ヨᩱࡣ⾑ᾮࢆ9,000×g㸪4°C ࡛ 5 ศ㛫㐲ᚰศ㞳ࡍࡿࡇ࡜࡟ࡼࡾᚓࡓࠋ

Wistar fattyࣛࢵࢺ࠾ࡼࡧWistar leanࣛࢵࢺࡢయ⤌ᡂࡣEchoMRITM_{900 (EchoMRI, ࢸ࢟ࢧࢫ) ࢆ⏝࠸}

࡚1 㐌㛫࡟ 1 ᅇホ౯ࡋ㸪ྠ᫬࡟య㔜ࡶ ᐃࡋࡓࠋయ⬡⫫⋡ࡣᘧ 4-1 ࡢィ⟬ᘧࢆ⏝࠸࡚ィ⟬ࡋࡓࠋ

య⬡⫫⋡ (%) =⥲⬡⫫㔜㔞 ( )

య㔜 ( ) × 100 ᘧ4-1

(36)

4.2.4 ⾑₢⺮ⓑ⤖ྜ

Wistar fatty ࣛࢵࢺ࠾ࡼࡧWistar lean ࣛࢵࢺ⾑₢୰ࡢ[14_{C]TAK-357 ࡢ 0.1 ࠾ࡼࡧ1 g/mL ࡟࠾ࡅࡿ⺮}

ⓑ⤖ྜ⋡ࡣin vitro ࡛㉸㐲ᚰἲ࡟ࡼࡗ࡚ホ౯ࡋࡓࠋࣈࣛࣥࢡ⾑₢ࡣవ๫ࣛࢵࢺ࠿ࡽ᥇ྲྀࡋࡓࠋ

4.2.5 ⃰ᗘ ᐃἲ

TAK-357 ࢆ⤒ཱྀᢞ୚ᚋࡢ⾑₢୰TAK-357 ⃰ᗘࡣᐃ㔞ୗ㝈2 ng/mL ࡢLC/MS/MS (API-4000, Applied Biosystems/MDS SCIEX) ࢆ⏝࠸࡚ᐃ㔞ࡋࡓࠋ⾑₢୰ࡢ TAK-357 ࡣ࣓ࢱࣀ࣮࡛ࣝ㝖⺮ⓑࡍࡿࡇ࡜࡟ࡼ

ࡾᢳฟࡋࡓࠋ㐲ᚰᚋ࡟ୖΎࢆ⛣ື┦࡛ᕼ㔘ࡋ㸪LC/MS/MS ࡟ὀධࡋࡓࠋ࣒࢝ࣛ࡟ࡣ Shim-pack XR-ODS ࣒࢝ࣛ(2.2 m, 2.0 × 30 mm㸪ᓥὠ〇సᡤ)ࢆ⏝࠸㸪50°C ࡟⥔ᣢࡋࡓࠋ⛣ື┦ A ࡟ࡣ 10 mmol/L 㓑㓟࢔ ࣥࣔࢽ࣒࢘Ỉ⁐ᾮ/ࢠ㓟 (100:0.2, v/v) ࢆ㸪⛣ື┦ B ࡟ࡣ࣓ࢱࣀ࣮ࣝࢆ⏝࠸ࡓࠋὶ㏿ࡣ 0.5 mL/min ࡟タ ᐃࡋ㸪ࢢࣛࢪ࢚ࣥࢺࡣୗグࡢ㏻ࡾ࡜ࡋࡓࠋ0.2 ศ㛫 10% B ࡛⥔ᣢࡋ㸪ࡑࡢᚋ 0.8 ศࡲ࡛࡟┤⥺ⓗ࡟ 95% B ࡲ࡛ୖ᪼ࡉࡏ㸪1.5 ศ㛫⥔ᣢࡉࡏࡓࠋࡑࡢᚋ 0.01 ศ࡛ 10% B ࡲ࡛పୗࡉࡏ㸪ṧࡾ 0.59 ศࢆ࠿ࡅ࡚ ᖹ⾮໬ࡋࡓࠋ1 ὀධࡢ⥲ࢧ࢖ࢡࣝ᫬㛫ࡣ 3.1 ศ㛫࡛࠶ࡗࡓࠋTAK-357 ࡣ MRM ࣮ࣔࢻ᳨࡛ฟࡋ㸪ࡑࡢ m/z ࡣ 381 191 ࡜ࡋࡓࠋࡇࡢศᯒἲࡢṇ☜ᛶ࠾ࡼࡧ⢭ᗘࡣࡑࢀࡒࢀ-16.0-3.6%࠾ࡼࡧ 3.8-10.0%࡛࠶ ࡗࡓࠋ ⾑₢㸪⬡⫫⤌⧊㸪ᒀ࠾ࡼࡧ⣅୰ࡢᨺᑕ⬟ࡣLSC ࡛ ᐃࡋࡓࠋ[14_{C]TAK-357 ࢆ㟼⬦ෆᢞ୚ᚋࡢ⾑₢} ୰௦ㅰ≀⤌ᡂศᯒ࡛ࡣᨺᑕᛶᡂศࢆ࢔ࢭࢺࢽࢺࣜࣝࡲࡓࡣ࢔ࢭࢺࢽࢺࣜࣝ/࢖ࢯࣉࣟࣃࣀ࣮ࣝ(1:2, v/v)࡛ᢳฟࡋࡓࠋ㐲ᚰᚋ࡟ୖΎࡣ❅⣲Ẽὶୗ࡛஝ᅛࡋ㸪⛣ື┦࡛෌ᵓ⠏ࡋࡓᚋ࡟࢜ࣥࣛ࢖ࣥᨺᑕ⬟ ᐃჾࢆ᥋⥆ࡋࡓHPLC ࡟ὀධࡋࡓࠋ࣒࢝ࣛ࡟ࡣ L-Column ODS column (5 μm, 250 mm × 4.6 mm㸪໬Ꮫ

≀㉁ホ౯◊✲ᶵᵓ) ࢆ⏝࠸㸪40°C ࡟⥔ᣢࡋࡓࠋ⛣ື┦ A ࡟ࡣ 10 mmol/L 㓑㓟࢔ࣥࣔࢽ࣒࢘/࢔ࢭࢺࢽ

ࢺࣜࣝࡢ9:1 ΰᾮࢆ㸪⛣ື┦ B ࡟ࡣ 10 mmol/L 㓑㓟࢔ࣥࣔࢽ࣒࢘/࢔ࢭࢺࢽࢺࣜࣝ 1:9 ΰᾮࢆ⏝࠸㸪ὶ

㔞ࢆ1 mL/min ࡜ࡋࡓࠋࢢࣛࢪ࢚ࣥࢺࣉࣟࢢ࣒ࣛ࡜ࡋ࡚ 50%⛣ື┦ B ࠿ࡽ㛤ጞࡋ㸪10 ศࡲ࡛࡟ 100%

⛣ື┦B ࡟┤⥺ⓗ࡟ୖ᪼ࡉࡏࡓࠋ15 ศ㛫 100%⛣ື┦B ࢆ⥔ᣢᚋ࡟50%⛣ື┦ B ࡟0.1 ศ㛫࡛ᡠࡋ㸪

(37)

4.2.6 ⸆≀ືែゎᯒ

ࣔࢹࣜࣥࢢ࡟ࡣNONMEM VI ࡢ FOCE with interaction ἲࢆ⏝࠸ࡓࠋPBPK ࣔࢹࣝࡣ➨ 3 ❶࡛ SD ࣛ

ࢵࢺ࠾ࡼࡧ࢖ࢾࡢPK ࢹ࣮ࢱࢆ⏝࠸࡚ᵓ⠏ࡋࡓࡶࡢࢆᇶᮏ࡜ࡋ㸪య㔜㸪㐌㱋㸪య⤌ᡂ࡞࡝ࢆཧ⪃࡟ᐇ

ࡢ⤌⧊㔜㔞ࡸሗ࿌್࡞࡝࠿ࡽ᭱㐺໬ࡋࡓ (15, 28, 56)ࠋ᫬㛫࡟౫Ꮡࡋࡓయ⤌ᡂࡢኚ໬ࡸయ㔜ቑຍࡶ⪃ ៖ࡋࡓࠋ᭱⤊ⓗ࡞PBPK ࣔࢹࣝࡣ Fig. 4-1 ࡟グ㍕ࡋࡓࠋ

ALAG ࡣ⤒ཱྀᢞ୚࠿ࡽᾘ໬⟶྾཰ࡀጞࡲࡿࡲ࡛ࡢࣛࢢࢱ࢖࣒ࢆ⾲ࡋ࡚࠸ࡿࠋWistar lean ࣛࢵࢺࡢ⤌ ⧊/⾑ᾮศ㓄ಀᩘ (Px್) ࡣ➨ 3 ❶࡛᥎ᐃࡋࡓ SD ࣛࢵࢺࡢ್ࢆ⏝࠸ࡓࠋWistar fatty ࣛࢵࢺ࡟࠾࠸࡚ࡣ Wistar lean ࣛࢵࢺ➼ࡢṇᖖື≀࡜ྠࡌ Px್࡛ࡣᐇ ࡢ⾑₢୰⃰ᗘ᥎⛣ࢆグ㏙ࡍࡿࡇ࡜ࡀ࡛ࡁ࡞࠿ࡗ ࡓࡓࡵ㸪⬡⫫⤌⧊㸪⫢⮚࠾ࡼࡧࡑࡢ௚ࡢ⤌⧊࡟࠾ࡅࡿศ㓄ಀᩘࡣࣔࢹࣝࣇ࢕ࢵࢸ࢕ࣥࢢ࡟ࡼࡾ᭱㐺໬ ࡋࡓࠋࡑࡢ௚ࡢࣃ࣓࣮ࣛࢱࡢ୙Ᏻᐃ࡞᥎ᐃࢆ㑊ࡅࡿࡓࡵ㸪Wistar fatty ࣛࢵࢺࡢ Px್ࡣ᭱㐺໬ᚋࡣᅛ ᐃࡋࡓࠋ཯᚟⤒ཱྀᢞ୚⩌ࡢ1 ᅇ┠ࡢ⾑₢୰᭚㟢ࡀࡑࡢ௚ࡢᢞ୚᫬ (༢ᅇ࠾ࡼࡧ཯᚟ᢞ୚⩌ࡢ 2 ᅇ┠௨ 㝆) ࡜ẚ㍑ࡋ࡚ప࠿ࡗࡓࡓࡵ㸪ࣂ࢖࢜࢔࣋࢖ࣛࣅࣜࢸ࢕ (F) ࡣࡑࡢ௚ࡢᢞ୚᫬࡜ࡣู࡟᥎ᐃࡋࡓࠋ

య⤌ᡂศᯒィ࡛ ᐃࡋࡓ㝖⬡⫫㔜㔞ࡣWistar fatty ࣛࢵࢺ࡜Wistar lean ࣛࢵࢺ࡛ྠ➼࡛࠶ࡗࡓࡓࡵ㸪

య㔜ࡢᕪࡣ⬡⫫㔜㔞ࡢᕪࡢࡳ࡛ㄝ࡛᫂ࡁࡿ࡜⪃࠼ࡽࢀࡓࠋࡑࡇ࡛㸪⬡⫫⤌⧊௨እࡢWistar fatty ࣛࢵ ࢺ⤌⧊㔜㔞ࡣWistar lean ࣛࢵࢺ࡜ྠࡌ࡜ࡳ࡞ࡋ㸪ᘧ 4-2, 4-3 ࢆ⏝࠸࡚ィ⟬ࡋࡓࠋ ࣛࢵࢺࡢಶయู⤌⧊㔜㔞 = ࣛࢵࢺᖹᆒ⤌⧊㔜㔞× ಶయูయ㔜 ࣛࢵࢺᖹᆒయ㔜 ᘧ4-2 Wistar fatty ࣛࢵࢺࡢ⬡⫫⤌⧊㔜㔞ࡣୗグࡢࡼ࠺࡟⟬ฟࡋࡓࠋ ࣛࢵࢺ = ࣛࢵࢺ × ࣛࢵࢺయ⬡⫫⋡ ࣛࢵࢺయ⬡⫫⋡ ᘧ4-3 ᚰᢿฟ㔞ࡣᘧ4-4 ࡢࡼ࠺࡟࢔࣓ࣟࢺ࣮ࣜ࡟ᚑ࠸ィ⟬ࡋࡓ (15)ࠋ ᚰᢿฟ㔞( / ) = 60 × 0.235 × య㔜 ( ) . ᘧ4-4

(38)

Wistar lean ࣛࢵࢺ⾑₢୰ࡢ௦ㅰ≀ࢹ࣮ࢱ࠾ࡼࡧ୧⣔⤫ࡢ᤼ἥࢹ࣮ࢱ࡟ࡘ࠸࡚ࡶ㸪࣐ࢫࣂࣛࣥࢫ࡟▩

┪ࡀ↓࠸ࡇ࡜ࢆ☜ㄆࡍࡿࡓࡵ࡟ࣔࢹࣝ໬ࡋ࡚ゎᯒࡋࡓࠋグ㏙ⓗ࡞ࢥࣥࣃ࣮ࢺ࣓ࣥࢺࣔࢹࣝࢆ௦ㅰ≀࠾

ࡼࡧ᤼ἥࣔࢹࣝ࡟⏝࠸ࡓࠋ⤖ᯝࡢ㡯࡟グ㍕ࡢ㏻ࡾ㸪Wistar fatty ࣛࢵࢺࡢ⾑₢୰ᨺᑕ⬟ᡂศࡢ࡯ࡰ඲࡚

ࡀᮍኚ໬య࡛࠶ࡗࡓࡓࡵ㸪ࡇࡢࣔࢹࣝゎᯒ࡛ࡣ⥲ᨺᑕ⬟⃰ᗘࢆᮍኚ໬య⃰ᗘ࡜ࡳ࡞ࡋࡓࠋ

4.2.7 ࢩ࣑࣮ࣗࣞࢩࣙࣥ

ࢩ࣑࣮ࣗࣞࢩࣙࣥ࡟ࡣBerkeley Madonna Ver. 8.3.8 ࢆ⏝࠸ࡓࠋ➨୍ࡢ᮲௳࡜ࡋ࡚ TAK-357 ࡢࡼ࠺࡟ పCLint (0.08 L/h) ࡟࠾࠸࡚㸪⫧‶≧ែ࡜ṇᖖ≧ែ࡟࠾ࡅࡿ 1 ᪥ 1 ᅇ㸪1 㐌㛫࡟ 1 ᅇ࠾ࡼࡧ 4 㐌㛫࡟ 1

ᅇ཯᚟ᢞ୚࡛ࡢ⾑₢୰⃰ᗘࢆẚ㍑ࡋࡓࠋ୍᪉㸪CLintࡀ㧗⬡⁐ᛶ⸆≀ࡢ⾑୰⃰ᗘ᥎⛣࡟୚࠼ࡿᙳ㡪ࢆ

᥎ ࡍࡿࡓࡵ࡟㸪㧗CLint᮲௳ (5 L/h) ࡛ 1 ᪥ 1 ᅇ཯᚟ᢞ୚ࡋࡓ㝿ࡢ⾑₢୰⃰ᗘẚ㍑ࡶᐇ᪋ࡋࡓࠋᮏゎ

ᯒ࡛ࡣ⬡⫫⤌⧊㔜㔞ࡢ㐪࠸ࡀPK ࡟୚࠼ࡿᙳ㡪ࢆホ౯ࡍࡿࡇ࡜ࡀ୺┠ⓗ࡛࠶ࡿࡓࡵ㸪CLintࡀ⫧‶≧ែ

࡜ṇᖖ≧ែ࠸ࡎࢀ࡟࠾࠸࡚ࡶࢩ࣑࣮ࣗࣞࢺࡢᮇ㛫୰୍ᐃࡢ್࡜タᐃࡋࡓࠋ⫧‶≧ែ࠾ࡼࡧṇᖖ≧ែࡢ

⏕⌮Ꮫⓗࣃ࣓࣮ࣛࢱࡣࡑࢀࡒࢀWistar fatty ࣛࢵࢺ࠾ࡼࡧ Wistar lean ࣛࢵࢺ࡜ᇶᮏⓗ࡟ྠ➼ࡢ್ࢆ⏝