オベチコール酸によるCYP1A2ダウンレギュレーションに関する研究
概要
༤ኈㄽᩥ
࢜࣋ࢳࢥ࣮ࣝ㓟ࡼࡿCYP1A2ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥ㛵ࡍࡿ◊✲
ᗈᓥᏛᏛ㝔་ṑ⸆ಖᏛ◊✲⛉
་ṑ⸆Ꮫᑓᨷ
⏕యᶵ⬟ศᏊືែᏛ◊✲ᐊ
▼⏣ ༓ᑜ
ᣦᑟᩍဨ ྂṊ ᘺ୍㑻
┠ḟ
␎ㄒ୍ぴ ......................................................................................................................................................... 3
⥴ゝ ................................................................................................................................................................. 4
ᮏㄽ ................................................................................................................................................................. 8
➨୍❶ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡢ CYP1A2 ᑐࡍࡿᙳ㡪............................................................................ 8
➨୍⠇ ᗎㄽ ......................................................................................................................................... 8
➨⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡢ CYP1A2 㜼ᐖ⬟ホ౯........................................................................... 10
➨୕⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀࣄࢺ⤖᥋╔⫢⣽⬊ࡢ CYP1A2 mRNA ཬࡧ௦ㅰάᛶཬࡰࡍᙳ㡪
............................................................................................................................................................... 11
➨ᅄ⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟᭚㟢ࡼࡿ⣽⬊Ṛࡢᙳ㡪 ................................................................... 15
ᑠᣓ ....................................................................................................................................................... 16
➨❶ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡢ CYP2B6 ཬࡧ CYP3A4 ᑐࡍࡿᙳ㡪 ................................................. 18
➨୍⠇ ᗎㄽ ....................................................................................................................................... 18
➨⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀࣄࢺ⤖᥋╔⫢⣽⬊ࡢ CYP2B6 mRNAࠊ௦ㅰάᛶཬࡰࡍᙳ㡪 19
➨୕⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀࣄࢺ⤖᥋╔⫢⣽⬊ࡢ CYP3A4 mRNAࠊ௦ㅰάᛶཬࡰࡍᙳ㡪 22
➨ᅄ⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡢ CYP3A4 ┤᥋㜼ᐖ⬟ࡢホ౯............................................................... 25
ᑠᣓ ....................................................................................................................................................... 26
➨୕❶ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀ㓝⣲ㄏᑟୗ CYP1A2 ࠾ࡼࡧ CYP1A2 ไᚚᅉᏊཬࡰࡍᙳ㡪 .......... 28
➨୍⠇ ᗎㄽ ....................................................................................................................................... 28
➨⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀ࣓࢜ࣉࣛࢰ࣮ࣝ㓝⣲ㄏᑟୗ CYP1A2 mRNAࠊ௦ㅰάᛶཬࡰࡍᙳ
㡪 ........................................................................................................................................................... 30
➨୕⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀ CYP1A2 ㌿ไᚚᅉᏊࡢ mRNA ཬࡰࡍᙳ㡪 ............................. 33
ᑠᣓ ....................................................................................................................................................... 34
⥲ㄽ ............................................................................................................................................................... 35
ᐇ㦂᪉ἲ ............................................................................................................................................... 38
ᘬ⏝ᩥ⊩ ....................................................................................................................................................... 42
ᮏㄽᩥ㛵㐃ࡋࡓᏛⓎ⾲ ....................................................................................................................... 47
ᮏㄽᩥࡢᇶ♏࡞ࡿཎⴭ ........................................................................................................................... 47
ㅰ㎡ ............................................................................................................................................................... 48
␎ㄒ୍ぴ
AhR㸸aryl hydrocarbon receptor
AhRR㸸aryl hydrocarbon receptor repressor
Arnt㸸aryl hydrocarbon receptor nuclear translocator
AUC㸸area under the concentration-time curve
AUC0–∞㸸area under the concentration-time curve from time zero to infinity
CAR㸸constitutive androstane receptor
CYP㸸cytochrome P450
DDI㸸drug-drug interactions
DMSO㸸dimethylsulfoxide
EMA㸸European Medicines Agency
FDA㸸U.S. Food and Drug Administration
FXR㸸farnesoid X receptor
GAPDH㸸glyceraldehyde-3-phosphate dehydrogenase
HPLC㸸high performance liquid chromatography
HSP90㸸heat shock protein 90
LC-MS/MS㸸HPLC tandem mass spectrometry
LDH㸸lactate dehydrogenase
LRH-1㸸liver receptor homologue-1
3-MC㸸3-methyl-cholanthrene
MSPK㸸mechanism-based static pharmacokinetic
β-NADPH㸸reduced β-nicotinamide adenine dinucleotide phosphate
OCA㸸obeticholic acid
PMDA㸸Pharmaceutical and Medical Devices Agency
PXR㸸pregnane X receptor
SHP㸸small heterodimer partner
TCDD㸸2,3,7,8-tetrachlorodibenzo-para-dioxin
XRE㸸xenobiotic responsive element
⥴ゝ
Cytochrome P450㸦CYP㸧ࡣ་⸆ရࢆྵࡴ⏕య␗≀ࢆ௦ㅰࡍࡿ㓝⣲࡛ࠊ་⸆ရࡢయෆࡽࡢᾘኻ
せ࡞ᙺࢆᯝࡓࡋ࡚࠸ࡿࠋCYP3A4 ࡣ⫢⮚࠾࠸࡚᭱ࡶከࡃⓎ⌧ࡋ࡚࠸ࡿศᏊ✀࡛࠶ࡾࠊࣄ
ࢺ⫢࣑ࢡࣟࢯ࣮࣒Ⓨ⌧ࡍࡿCYPࡢ⣙16%ࢆ༨ࡵࡿࠋࡲࡓࠊ⫢⮚ࡣCYP3A4௨እࡶCYP1A2ࠊ
CYP2A6ࠊCYP2B6ࠊCYP2C8ࠊCYP2C9ࠊCYP2D6ཬࡧCYP2E1࡞ᵝࠎ࡞ศᏊ✀ࡀⓎ⌧ࡋ࡚࠸ࡿ
㸦Kawakami et al., 2010㸧ࠋࡇࡢ࠺ࡕࣄࢺయෆ࡛⸆≀௦ㅰࢆᢸࡗ࡚࠸ࡿせ࡞ศᏊ✀ࡣࡑࡢⓎ⌧㔞
࠾ࡼࡧ་⸆ရࡢᏛᵓ㐀ࡢᇶ㉁≉␗ᛶ౫Ꮡࡋ࡚ỴᐃࡉࢀࠊCYP3A4ࠊCYP2D6ࠊCYP2C9ࠊ
CYP1A2࠾ࡼࡧCYP2B6➼ࡀᣲࡆࡽࢀࡿ㸦Zanger et al., 2013㸧ࠋ
་⸆ရࡼࡿCYPࡢ௦ㅰάᛶኚࡣ⸆≀㛫┦స⏝㸦drug-drug interactions㸹DDI㸧ࡢ1ࡘ࡛࠶ࡾࠊ
ኚືᑐ㇟ࡢCYP࡛௦ㅰࡉࢀࡿే⏝་⸆ရࡢ⸆≀ືែᙳ㡪ࢆ࠼ࠊᮇᚅࡋ࡚࠸ࡓ⸆ຠࢆῶᙅࡉࡏ
ࡓࡾ㔜⠜࡞స⏝ࢆច㉳ࡉࡏࡓࡾࡍࡿ࠾ࡑࢀࡀ࠶ࡿ㸦Pelkonen et al., 2008㸹Yu et al., 2018㸧ࠋ⮫ᗋ
࡛ࡣ⒪ࡢࡓࡵ」ᩘࡢ་⸆ရࢆే⏝ฎ᪉ࡍࡿࡇࡀከ࠸ࡇࡽࠊྛ་⸆ရࡢDDIࣜࢫࢡࡀ㐺
ษホ౯ࡉࢀሗᥦ౪ࡉࢀࡿࡇࡣࠊ⮫ᗋ࠾ࡅࡿ་⸆ရࡢ㐺ṇ⏝ࡗ࡚㔜せ࡛࠶ࡿࠋ⸆
ࡢ⌧ሙ࡛࠶ࡿ〇⸆ᴗࡀ᪂⸆ࢆ㛤Ⓨࡍࡿ࠶ࡓࡗ࡚ࡣࠊ་⸆ရೃ⿵ྜ≀ࡢᣢࡕ࠺ࡿDDIࡢᛶ㉁
ࡑࡢ⛬ᗘࢆ㐺ษண ホ౯ࡍࡿࡇࡣᚲ㡲࡛࠶ࡾࠊண ⢭ᗘࡀ㛤Ⓨྜ≀ࡢ㛤Ⓨ୰Ṇ┤⤖ࡍ
ࡿ༴㝤ᛶࡶ࠶ࡿࠋ
〇⸆ᴗࡀ་⸆ရೃ⿵ྜ≀ࡢDDIࣜࢫࢡࢆホ౯ࡍࡿ㝿ࠊྛつไᙜᒁ㸦European Medicines
Agency 㸦EMA㸧ࠊU.S. Food and Drug Administration㸦FDA㸧ࠊPharmaceutical and Medical Devices
Agency㸦PMDA㸧㸧ࡢDDI࢞ࢲࣥࢫ࠾ࡼࡧ࢞ࢻࣛࣥࢆཧ↷ࡍࡿࠋྛDDI࢞ࢲࣥࢫ࠾ࡼࡧ࢞
ࢻࣛࣥࡣࠊᶆ‽ⓗ࡞ in vitro ホ౯᪉ἲࡸ⮫ᗋヨ㦂ࡢࢹࢨࣥ࠾ࡼࡧពᛮỴᐃࡢุ᩿ᇶ‽
࡞ࡿ࢝ࢵࢺ࢜ࣇ್ࡸỴᐃᶞࡀᙜࡢ⛉Ꮫⓗ⫼ᬒࢆ㋃ࡲ࠼࡚ྍ⬟࡞㝈ࡾヲ⣽♧ࡉࢀ࡚࠸ࡿࠋ
࠼ࡤࠊ㓝⣲ㄏᑟࡣCYPࡢ㌿άᛶࢆಁ㐍ࡍࡿࡇ࡛ࡑࡢάᛶࢆቑࡉࡏࠊ⿕┦స⏝⸆ࡢ⾑₢
୰⃰ᗘ࠾ࡼࡧ⾑୰⃰ᗘ-㛫᭤⥺ୗ㠃✚㸦Area under the concentration-time curve㸹AUC㸧ࢆపୗࡉࡏ
ࡿ࠾ࡑࢀࡢ࠶ࡿDDIࡢ୍✀࡛࠶ࡿࡀࠊ་⸆ရೃ⿵ྜ≀ࡢ㓝⣲ㄏᑟホ౯࡛ࡣin vitroホ౯ࡼࡗ࡚
ᚓࡽࢀࡿࣃ࣓࣮ࣛࢱࢆ⏝࠸ࡓุ᩿ࡸ㟼ⓗ⸆≀㏿ᗘㄽࣔࢹࣝࠊ⏕⌮Ꮫⓗ⸆≀㏿ᗘㄽࣔࢹࣝࢆά⏝ࡋ
ࡓุ᩿࡞ࠊ」ᩘࡢᡭἲࢆẁ㝵ⓗά⏝ࡍࡿỴᐃᶞᚑࡗ࡚⮫ᗋ⸆≀┦స⏝ヨ㦂ࡢᚲせᛶࢆ᳨
ウࡍࡿࡇࡀ࡛ࡁࡿࠋࡲࡓࠊin vitroホ౯ᡭἲᑐࡋ࡚ࡶࠊࣄࢺ⤖᥋╔⫢⣽⬊ࢆ⏝࠸ࡓCYP1A2ࠊ
CYP2B6ཬࡧCYP3A4㸦CYP3A4࡛㓝⣲ㄏᑟࡀㄆࡵࡽࢀࡓሙྜࡣCYP2C⣔ࡢศᏊ✀ࡘ࠸࡚ࡶᐇ㸧
ࡢmRNAⓎ⌧ኚື࠾ࡼࡧ௦ㅰάᛶኚືࢆホ౯ࡍࡿ᪨ࡀ࣏ࢪࢸࣈࢥࣥࢺ࣮ࣟࣝࡢྜ≀ඹ
グ㍕ࡉࢀ࡚࠸ࡿࠋྛDDIࡢ࣓࢝ࢽࢬ࣒ࡸin vitro-in vivoእᤄᛶࡢᇶ♏◊✲ࡀ᥎㐍ࡉࢀ▱ぢࡀ῝ࡲࡿ
ࡇ࡛ࠊDDI࢞ࢲࣥࢫ࠾ࡼࡧ࢞ࢻࣛࣥࡢุ᩿ᇶ‽ࡸỴᐃᶞࡀᨵၿࡉࢀࡿࡇࡣࠊ㛤Ⓨྜ≀
ࡀ᭷ࡍࡿ⮫ᗋDDIࣜࢫࢡࡢண ⢭ᗘྥୖࡘ࡞ࡀࡾࠊ᭱⤊ⓗࡣ་⸆ရ㛤Ⓨࡢᡂຌ☜⋡ࡢୖ᪼࠾
ࡼࡧ་⸆ရࡢ㐺ṇ⏝㈉⊩ࡍࡿࡶࡢᮇᚅࡉࢀࡿࠋ
CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣ㓝⣲ㄏᑟ㏫ࡢ⌧㇟࡛ࠊCYPࡢ㌿άᛶࢆᢚไࡍࡿࡇ࡛ά
ᛶࢆῶᑡࡉࡏ⿕┦స⏝⸆ࡢ⾑₢୰⃰ᗘ࠾ࡼࡧAUCࢆቑຍࡉࡏࡿ࠾ࡑࢀࡢ࠶ࡿDDI࡛࠶ࡿ㸦Fig. 1㸧ࠋ
CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥྠᵝCYPࡢάᛶࢆῶᑡࡉࡏࡿࡇ࡛⿕┦స⏝⸆ࡢ⾑₢୰⃰ᗘ
ࡸAUCࢆቑຍࡉࡏࡿྍ⬟ᛶࡀ࠶ࡿDDIࡋ࡚ࡣࠊCYP㜼ᐖࡀ▱ࡽࢀ࡚࠸ࡿࠋ
Fig. 1. Change of pharmacokinetic profile with typical CYP substrate (Conceptional figure).
CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣ㓝⣲ㄏᑟࡸ㜼ᐖࡣ␗࡞ࡾࠊ་⸆ရࡼࡿሗ࿌ࡀᑡ࡞ࡃ
DDI◊✲࠾࠸࡚᪂ࡋ࠸ศ㔝࡛࠶ࡾࠊ⤫ྜⓗ࡞⌮ゎࡀᚓࡽࢀ࡚࠸࡞࠸ࠋⴭ⪅ࡣࠊሗ࿌ࡉࢀࡿㄽᩥࢆ
࣮࣋ࢫ་⸆ရ࠾ࡼࡧ་⸆ရೃ⿵ྜ≀ࡼࡗ࡚CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀ♧၀ࡉࢀࡿ
ࢆ㞟⣙ࡋࡓ㸦Table 1㸧ࠋ࠼ࡤࠊSagerࡽࡣࣄࢺin vivo ࡛ࣈࣉࣟࣆ࢜ࣥࢆే⏝ࡋࡓሙྜCYP2D6
ᆺᇶ㉁ࡢAUCୖ᪼ࡀㄆࡵࡽࢀࡓ⌧㇟ࡘ࠸࡚ࠊin vitro࡛ㄆࡵࡽࢀࡓࣈࣉࣟࣆ࢜ࣥཬࡧࡑࡢ௦ㅰ
≀ࡼࡿᙅ࠸CYP2D6㜼ᐖ⬟ࡔࡅ࡛ࡣㄝ࡛᫂ࡁ࡞࠸⪃࠼ࠊࣄࢺ᥋╔⫢⣽⬊ࢆ⏝࠸࡚ࣈࣉࣟࣆ࢜
ࣥ࠾ࡼࡧࣈࣉࣟࣆ࢜ࣥࡢ௦ㅰ≀ࡀin vitro CYP2D6ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢ࣏ࢸࣥࢩࣕࣝࢆ᭷ࡋ
࡚࠸ࡿࡇࢆⓎぢࡋࠊ㜼ᐖࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢ୧᪉ࢆ⪃៖ࡍࡿࡇ࡛in vitroࡽin vivo
ࡢண ⢭ᗘࡀྥୖࡋࡓሗ࿌ࡋ࡚࠸ࡿ㸦Sager et al., 2017㸧ࠋࡉࡽࣇࢨ࣮♫ࡢ㛤Ⓨྜ≀
LY2090314ࡣࠊ⣽⬊Ṛ࠾ࡼࡧ㜼ᐖࢆ㉳ࡇࡉ࡞࠸⃰ᗘ࡛ࣄࢺ⤖᥋╔⫢⣽⬊ࡢCYP2B6 mRNA࠾ࡼࡧ
௦ㅰάᛶࢆῶᑡࡉࡏࠊCYP1A2ࡸCYP3A4ࡣᙳ㡪ࢆ࠼࡞࠸ࡇࡽࠊCYP2B6ࢆ≉␗ⓗࢲ࢘
ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡉࡏࡿྍ⬟ᛶࡀ♧၀ࡉࢀ࡚࠸ࡿ㸦Zamek-Gliszczynski et al., 2014㸧ࠋࡋࡋ࡞
ࡀࡽࠊࣄࢺ⤖᥋╔⫢⣽⬊ࢆ⏝࠸ࡓin vitroホ౯࡛ㄆࡵࡽࢀࡓ13-ࢩࢫ-ࣞࢳࣀࣥ㓟ࡼࡿCYP2D6
ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣࣄࢺin vivoࡣᫎࡉࢀ࡞ࡗࡓ࠸࠺ሗ࿌ࡶ࠶ࡿ㸦Stevison et al.,
2019㸧ࠋࡇࡢࡼ࠺ࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢin vitro-in vivoእᤄᛶࢆ᳨ドࡍࡿࡣᩘ
ࡀ༑ศ࡛࠶ࡿࡢࡀ⌧≧࡛࠶ࡿࠋ
᪥ᮏࡢࠕ་⸆ရ㛤Ⓨ㐺ṇ࡞ሗᥦ౪ࡢࡓࡵࡢ⸆≀┦స⏝࢞ࢻࣛࣥ㛵ࡍࡿ㉁ᛂ⟅㞟
㸦Q&A㸧࡛ࠖࡣࠊin vitro㓝⣲ㄏᑟヨ㦂࡛mRNAࡀᑐ↷⩌ᑐࡋ࡚⃰ᗘ౫Ꮡⓗ50%௨ୖῶᑡࡋࠊࡑ
ࢀࡀ⣽⬊ẘᛶ㉳ᅉࡍࡿࡶࡢ࡛ࡣ࡞࠸⪃࠼ࡽࢀࡿሙྜࠊヱᙜࡍࡿ㓝⣲ࡢࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙ
ࣥࡀ♧၀ࡉࢀࡿࡀࠊ⌧≧࡛ࡣ⸆≀ࡼࡾ⏕ࡌࡿࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥⓎ⌧࣓࢝ࢽࢬ࣒㛵ࡍ
ࡿ▱ぢࡣ㝈ᐃⓗ࡛࠶ࡿࡓࡵࠊin vitro࡛⃰ᗘ౫Ꮡⓗ࡞ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀほᐹࡉࢀࡓሙྜࡣ
⮫ᗋ⸆≀┦స⏝ヨ㦂᳨࡛ウࡍࡿࡇࡀ᥎ዡࡉࢀࡿ᪨ࡀ᫂グࡉࢀ࡚࠸ࡿࠋࡲࡓࠊEMA࢞ࢻࣛ
࡛ࣥࡶྠᵝࡢグ㍕ࡀ࡞ࡉࢀ࡚࠾ࡾࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥ㛵ࡍࡿホ౯ࡢࡓࡵࡢỴᐃᶞࡣࠊ
▱ぢࡀ༑ศ࡛ࡣ࡞ࡃࠊ࠸ࡲࡔᡂ⇍ࡋ࡚࠸࡞࠸⪃࠼ࡽࢀࡿࠋ
Table 1
Observations of CYP down-regulation by drugs and new chemical entities.
Compounds
Enzymes
Animals
in vitro/ in vivo
References
sulpiride
CYP1A2
rat
in vivo
Harkitis et al., PLoS ONE. 2015
CYP1A1
CYP1B1
telithromycin
CYP1A2
rat
in vivo
Nosaka et al., Life Sciences. 2006
CYP3A2
LY2090314
CYP2B6
human
in vitro (hepatocyte)
Zamek-Gliszczynski et al., Drug Metab Dispos. 2014
metformin
CYP2B6
human
in vitro (hepatocyte)
Yang et al., Mol Pharmacol. 2014
carfilzomib
CYP3A4
human
in vitro (hepatocyte)
Wang et al., Drug Metab Dispos. 2013
GW4064
CYP3A4
human
in vitro (hepatocyte)
Zhang et al., Drug Metab Dispos. 2015
metformin
CYP3A4
mouse
in vivo
Krausova et al., Biochem Pharmacol. 2001
human
in vitro (hepatocyte)
capecitabine
CYP2C9
human
in vivo
Ramírez et al., Clinical Pharmacol. 2019
fluorouracil
CYP2C9
human
in vivo
Gilbar et al., Ann Pharmacother. 2001
bupropion
CYP2D6
human
in vitro (hepatocyte, HepG2)
Sager et al., Biochem Pharmacol. 2017
in vivo
GW4064
CYP2D6
mouse
in vivo
Pan et al., Drug Metab Dispos. 2015
୍᪉࡛ࠊᾏእࡢᡭ〇⸆ᴗ➼ࡀཧຍࡋ࡚࠸ࡿInnovation and Qualityࢥࣥࢯ࣮ࢩ࣒ࡢDrug
Metabolism Leadership Groupࡣࠊ་⸆ရ㛤Ⓨࡢ⸆≀ືែࢫࢡ࣮ࣜࢽࣥࢢࡋ࡚ᐇࡉࢀࡓin vitroㄏ
ᑟヨ㦂యࡢ࠺ࡕ10ࡽ20%࡛CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀ☜ㄆࡉࢀࡓ࠸࠺ࣥࢣ࣮ࢺ⤖ᯝ
ࢆሗ࿌ࡋ࡚࠸ࡿ㸦Hariparsad et al., 2017㸧ࠋࡲࡓࠊྠሗ࿌࠾࠸࡚ᑐ㇟ศᏊ✀ࡣࠊ㓝⣲ㄏᑟ࡛ホ౯
ᑐ㇟࡞ࡗ࡚࠸ࡿศᏊ✀ࡢ࡚ࡢศᏊ✀ࡀྵࡲࢀ࡚࠾ࡾ㸦 CYP1A2, 27.3%; CYP2B6, 27.3%;
CYP3A4, 36.4%; CYP2C8/9, 6.8%㸧ࠊ⌧ᅾ㛤Ⓨ୰ࡢ་⸆ရೃ⿵ྜ≀ࡼࡗ࡚CYPࢲ࢘ࣥࣞࢠࣗࣞ
࣮ࢩࣙࣥࡣ≉ᐃࡢศᏊ✀೫ࡿࡇ࡞ࡃ㉳ࡇࡾᚓࡿྍ⬟ᛶࡀ♧ࡉࢀ࡚࠸ࡿࠋࡍ࡞ࢃࡕࠊ་⸆ရ㛤
Ⓨ⌧ሙ࠾࠸࡚ࡣᑡ࡞ࡽࡎin vitro CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀㄆࡵࡽࢀࡿࡀሗ࿌ࡉࢀ࡚
࠾ࡾࠊྛ〇⸆ᴗࡣin vitroࡢ㓝⣲ㄏᑟࢫࢡ࣮ࣜࢽࣥࢢ࡛⃰ᗘ౫Ꮡⓗ࡞CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙ
ࣥࡀ་⸆ရೃ⿵ྜ≀࡛ㄆࡵࡽࢀࡓሙྜࡣࠊᑡ࡞࠸▱ぢࡽࡑࡢ࣓࢝ࢽࢬ࣒ࡸ⮫ᗋ࠾ࡅࡿᙳ
㡪ࢆ⪃៖ࡋ࡞ࡅࢀࡤ࡞ࡽ࡞࠸ࡢࡀ⌧≧࡛࠶ࡿࠋࡋࡓࡀࡗ࡚ࠊࡇࢀࡲ࡛ࡢࣄࢺin vivo⮫ᗋ⸆≀┦స
⏝ヨ㦂ࡢ⤖ᯝ࡞ࡽࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࢆᘬࡁ㉳ࡇࡋ࡚࠸ࡿྍ⬟ᛶࡀ࠶ࡿࢆ㞟
⣙ࡋࠊࡑࢀࢆ᳨ドྜ≀ࡋ࡚in vitro࡛ࡢ࣓࢝ࢽࢬ᳨࣒ドࡸࠊin vivoࡢእᤄࢆ᳨ドࡋ࡚࠸ࡃࡇ
ࡣ㔜せ࡛࠶ࡿ⪃࠼ࡽࢀࡿࠋ
ᮏ◊✲࡛ࡣࠊCYP1A2ࡢᆺᇶ㉁࡛࠶ࡿ࢝ࣇ࢙ࣥཎⓎᛶ⫹Ồᛶ⫹⟶⅖⒪࡛࠶ࡿ࢜࣋ࢳ
ࢥ࣮ࣝ㓟㸦Fig. ...