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◊✲








ᗈᓥ኱Ꮫ኱Ꮫ㝔་ṑ⸆ಖ೺Ꮫ◊✲⛉
་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 ཬࡧ௦ㅰάᛶ࡟ཬࡰࡍᙳ㡪
............................................................................................................................................................... 11
➨ᅄ⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟᭚㟢࡟ࡼࡿ⣽⬊Ṛ࡬ࡢᙳ㡪 ................................................................... 15
ᑠᣓ ....................................................................................................................................................... 16
➨஧❶ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡢ CYP2B6 ཬࡧ CYP3A4 ࡟ᑐࡍࡿᙳ㡪 ................................................. 18
➨୍⠇ ᗎㄽ ....................................................................................................................................... 18
➨஧⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀࣄࢺ෾⤖᥋╔⫢⣽⬊ࡢ CYP2B6 mRNAࠊ௦ㅰάᛶ࡟ཬࡰࡍᙳ㡪 19
➨୕⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀࣄࢺ෾⤖᥋╔⫢⣽⬊ࡢ CYP3A4 mRNAࠊ௦ㅰάᛶ࡟ཬࡰࡍᙳ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 ไᚚᅉᏊ࡟ཬࡰࡍᙳ㡪 .......... 28
➨୍⠇ ᗎㄽ ....................................................................................................................................... 28
➨஧⠇ ࢜࣋ࢳࢥ࣮ࣝ㓟ࡀ࣓࢜ࣉࣛࢰ࣮ࣝ㓝⣲ㄏᑟୗ CYP1A2 mRNAࠊ௦ㅰάᛶ࡟ཬࡰࡍᙳ
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་⸆ရࡢయෆ࠿ࡽࡢᾘኻ
࡟୺せ࡞ᙺ๭ࢆᯝࡓࡋ࡚࠸ࡿࠋCYP3A4 ࡣ⫢⮚࡟࠾࠸࡚᭱ࡶከࡃⓎ⌧ࡋ࡚࠸ࡿศᏊ✀࡛࠶ࡾࠊࣄ
ࢺ⫢࣑ࢡࣟࢯ࣮࣒࡟Ⓨ⌧ࡍࡿCYPࡢ⣙16%ࢆ༨ࡵࡿࠋࡲࡓࠊ⫢⮚࡟ࡣCYP3A4௨እ࡟ࡶCYP1A2ࠊ
CYP2A6ࠊCYP2B6ࠊCYP2C8ࠊCYP2C9ࠊCYP2D6ཬࡧCYP2E1࡞࡝ᵝࠎ࡞ศᏊ✀ࡀⓎ⌧ࡋ࡚࠸ࡿ
㸦Kawakami et al., 2010㸧ࠋࡇࡢ࠺ࡕࣄࢺయෆ࡛⸆≀௦ㅰࢆᢸࡗ࡚࠸ࡿ୺せ࡞ศᏊ✀ࡣࡑࡢⓎ⌧㔞
࠾ࡼࡧ་⸆ရࡢ໬Ꮫᵓ㐀࡜ࡢᇶ㉁≉␗ᛶ࡟౫Ꮡࡋ࡚ỴᐃࡉࢀࠊCYP3A4ࠊCYP2D6ࠊCYP2C9ࠊ
CYP1A2࠾ࡼࡧCYP2B6➼ࡀᣲࡆࡽࢀࡿ㸦Zanger et al., 2013㸧ࠋ
 ་⸆ရ࡟ࡼࡿCYPࡢ௦ㅰάᛶኚ໬ࡣ⸆≀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⏝ฎ᪉ࡍࡿࡇ࡜ࡀከ࠸ࡇ࡜࠿ࡽࠊྛ་⸆ရࡢDDIࣜࢫࢡࡀ㐺
ษ࡟ホ౯ࡉࢀ᝟ሗᥦ౪ࡉࢀࡿࡇ࡜ࡣࠊ⮫ᗋ࡟࠾ࡅࡿ་⸆ရࡢ㐺ṇ౑⏝࡟࡜ࡗ࡚㔜せ࡛࠶ࡿࠋ๰⸆
ࡢ⌧ሙ࡛࠶ࡿ〇⸆௻ᴗࡀ᪂⸆ࢆ㛤Ⓨࡍࡿ࡟࠶ࡓࡗ࡚ࡣࠊ་⸆ရೃ⿵໬ྜ≀ࡢᣢࡕ࠺ࡿDDIࡢᛶ㉁
࡜ࡑࡢ⛬ᗘࢆ㐺ษ࡟ண ホ౯ࡍࡿࡇ࡜ࡣᚲ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ࡢDDI࢞࢖ࢲࣥࢫ࠾ࡼࡧ࢞࢖ࢻࣛ࢖ࣥࢆཧ↷ࡍࡿࠋྛDDI࢞࢖ࢲࣥࢫ࠾ࡼࡧ࢞
࢖ࢻࣛ࢖ࣥ࡟ࡣࠊᶆ‽ⓗ࡞ in vitro ホ౯᪉ἲࡸ⮫ᗋヨ㦂ࡢࢹࢨ࢖ࣥ࠾ࡼࡧពᛮỴᐃ᫬ࡢุ᩿ᇶ‽
࡜࡞ࡿ࢝ࢵࢺ࢜ࣇ್ࡸỴᐃᶞࡀᙜ᫬ࡢ⛉Ꮫⓗ⫼ᬒࢆ㋃ࡲ࠼࡚ྍ⬟࡞㝈ࡾヲ⣽࡟♧ࡉࢀ࡚࠸ࡿࠋ౛
࠼ࡤࠊ㓝⣲ㄏᑟࡣCYPࡢ㌿෗άᛶ໬ࢆಁ㐍ࡍࡿࡇ࡜࡛ࡑࡢάᛶࢆቑ኱ࡉࡏࠊ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౯࡟ࡼࡗ࡚
ᚓࡽࢀࡿࣃ࣓࣮ࣛࢱࢆ⏝࠸ࡓุ᩿ࡸ㟼ⓗ⸆≀㏿ᗘㄽࣔࢹࣝࠊ⏕⌮Ꮫⓗ⸆≀㏿ᗘㄽࣔࢹࣝࢆά⏝ࡋ
ࡓุ᩿࡞࡝ࠊ」ᩘࡢᡭἲࢆẁ㝵ⓗ࡟ά⏝ࡍࡿỴᐃᶞ࡟ᚑࡗ࡚⮫ᗋ⸆≀┦஫స⏝ヨ㦂ࡢᚲせᛶࢆ᳨
ウࡍࡿࡇ࡜ࡀ࡛ࡁࡿࠋࡲࡓࠊin vitroホ౯ᡭἲ࡟ᑐࡋ࡚ࡶࠊࣄࢺ෾⤖᥋╔⫢⣽⬊ࢆ⏝࠸ࡓCYP1A2ࠊ
CYP2B6ཬࡧCYP3A4㸦CYP3A4࡛㓝⣲ㄏᑟࡀㄆࡵࡽࢀࡓሙྜࡣCYP2C⣔ࡢศᏊ✀࡟ࡘ࠸࡚ࡶᐇ᪋㸧
ࡢmRNAⓎ⌧ኚື࠾ࡼࡧ௦ㅰάᛶኚືࢆホ౯ࡍࡿ᪨ࡀ࣏ࢪࢸ࢕ࣈࢥࣥࢺ࣮ࣟࣝࡢ໬ྜ≀౛࡜ඹ࡟
グ㍕ࡉࢀ࡚࠸ࡿࠋྛDDIࡢ࣓࢝ࢽࢬ࣒ࡸin vitro-in vivoእᤄᛶࡢᇶ♏◊✲ࡀ᥎㐍ࡉࢀ▱ぢࡀ῝ࡲࡿ
ࡇ࡜࡛ࠊDDI࢞࢖ࢲࣥࢫ࠾ࡼࡧ࢞࢖ࢻࣛ࢖ࣥࡢุ᩿ᇶ‽ࡸỴᐃᶞࡀᨵၿࡉࢀࡿࡇ࡜ࡣࠊ㛤Ⓨ໬ྜ≀
ࡀ᭷ࡍࡿ⮫ᗋDDIࣜࢫࢡࡢண ⢭ᗘྥୖ࡟ࡘ࡞ࡀࡾࠊ᭱⤊ⓗ࡟ࡣ་⸆ရ㛤Ⓨࡢᡂຌ☜⋡ࡢୖ᪼࠾
ࡼࡧ་⸆ရࡢ㐺ṇ౑⏝࡟㈉⊩ࡍࡿࡶࡢ࡜ᮇᚅࡉࢀࡿࠋ













CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣ㓝⣲ㄏᑟ࡜㏫ࡢ⌧㇟࡛ࠊCYPࡢ㌿෗άᛶ໬ࢆᢚไࡍࡿࡇ࡜࡛ά
ᛶࢆῶᑡࡉࡏ⿕┦஫స⏝⸆ࡢ⾑₢୰⃰ᗘ࠾ࡼࡧAUCࢆቑຍࡉࡏࡿ࠾ࡑࢀࡢ࠶ࡿDDI࡛࠶ࡿ㸦Fig. 1㸧ࠋ
CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥ࡜ྠᵝ࡟CYPࡢάᛶࢆῶᑡࡉࡏࡿࡇ࡜࡛⿕┦஫స⏝⸆ࡢ⾑₢୰⃰ᗘ
ࡸAUCࢆቑຍࡉࡏࡿྍ⬟ᛶࡀ࠶ࡿDDI࡜ࡋ࡚ࡣࠊCYP㜼ᐖࡀ▱ࡽࢀ࡚࠸ࡿࠋ

Fig. 1. Change of pharmacokinetic profile with typical CYP substrate (Conceptional figure).
CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣ㓝⣲ㄏᑟࡸ㜼ᐖ࡜ࡣ␗࡞ࡾࠊ་⸆ရ࡟ࡼࡿሗ࿌஦౛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⏝ࡋࡓሙྜ࡟CYP2D6
඾ᆺᇶ㉁ࡢAUCୖ᪼ࡀㄆࡵࡽࢀࡓ⌧㇟࡟ࡘ࠸࡚ࠊin vitro࡛ㄆࡵࡽࢀࡓࣈࣉࣟࣆ࢜ࣥཬࡧࡑࡢ௦ㅰ
≀࡟ࡼࡿᙅ࠸CYP2D6㜼ᐖ⬟ࡔࡅ࡛ࡣㄝ࡛᫂ࡁ࡞࠸࡜⪃࠼ࠊࣄࢺ᥋╔⫢⣽⬊ࢆ⏝࠸࡚ࣈࣉࣟࣆ࢜
ࣥ࠾ࡼࡧࣈࣉࣟࣆ࢜ࣥࡢ௦ㅰ≀ࡀin vitro CYP2D6ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢ࣏ࢸࣥࢩࣕࣝࢆ᭷ࡋ
࡚࠸ࡿࡇ࡜ࢆⓎぢࡋࠊ㜼ᐖ࡜ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢ୧᪉ࢆ⪃៖ࡍࡿࡇ࡜࡛in vitro࠿ࡽin vivo࡬
ࡢண ⢭ᗘࡀྥୖࡋࡓ࡜ሗ࿌ࡋ࡚࠸ࡿ㸦Sager et al., 2017㸧ࠋࡉࡽ࡟ࣇ࢓࢖ࢨ࣮♫ࡢ㛤Ⓨ໬ྜ≀
LY2090314ࡣࠊ⣽⬊Ṛ࠾ࡼࡧ㜼ᐖࢆ㉳ࡇࡉ࡞࠸⃰ᗘ࡛ࣄࢺ෾⤖᥋╔⫢⣽⬊ࡢCYP2B6 mRNA࠾ࡼࡧ
௦ㅰάᛶࢆῶᑡࡉࡏࠊCYP1A2ࡸCYP3A4࡟ࡣᙳ㡪ࢆ୚࠼࡞࠸ࡇ࡜࠿ࡽࠊCYP2B6ࢆ≉␗ⓗ࡟ࢲ࢘
ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡉࡏࡿྍ⬟ᛶࡀ♧၀ࡉࢀ࡚࠸ࡿ㸦Zamek-Gliszczynski et al., 2014㸧ࠋࡋ࠿ࡋ࡞
ࡀࡽࠊࣄࢺ෾⤖᥋╔⫢⣽⬊ࢆ⏝࠸ࡓin vitroホ౯࡛ㄆࡵࡽࢀࡓ13-ࢩࢫ-ࣞࢳࣀ࢖ࣥ㓟࡟ࡼࡿCYP2D6
ࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡣࣄࢺin vivo࡟ࡣ཯ᫎࡉࢀ࡞࠿ࡗࡓ࡜࠸࠺ሗ࿌ࡶ࠶ࡿ㸦Stevison et al.,
2019㸧ࠋࡇࡢࡼ࠺࡟ࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡢin vitro-in vivoእᤄᛶࢆ᳨ドࡍࡿ࡟ࡣ஦౛ᩘ
ࡀ୙༑ศ࡛࠶ࡿࡢࡀ⌧≧࡛࠶ࡿࠋ
᪥ᮏࡢࠕ་⸆ရ㛤Ⓨ࡜㐺ṇ࡞᝟ሗᥦ౪ࡢࡓࡵࡢ⸆≀┦஫స⏝࢞࢖ࢻࣛ࢖ࣥ࡟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ࡍࡿࡇ࡜ࡀ᥎ዡࡉࢀࡿ᪨ࡀ᫂グࡉࢀ࡚࠸ࡿࠋࡲࡓࠊEMA࢞࢖ࢻࣛ࢖
࡛ࣥࡶྠᵝࡢグ㍕ࡀ࡞ࡉࢀ࡚࠾ࡾࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥ࡟㛵ࡍࡿホ౯ࡢࡓࡵࡢỴᐃᶞࡣࠊ
▱ぢࡀ༑ศ࡛ࡣ࡞ࡃࠊ࠸ࡲࡔ࡟ᡂ⇍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

୍᪉࡛ࠊᾏእࡢ኱ᡭ〇⸆௻ᴗ➼ࡀཧຍࡋ࡚࠸ࡿInnovation and Qualityࢥࣥࢯ࣮ࢩ࢔࣒ࡢDrug
Metabolism Leadership Groupࡣࠊ་⸆ရ㛤Ⓨࡢ⸆≀ືែࢫࢡ࣮ࣜࢽࣥࢢ࡜ࡋ࡚ᐇ᪋ࡉࢀࡓin vitroㄏ
ᑟヨ㦂඲యࡢ࠺ࡕ10࠿ࡽ20%࡛CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀ☜ㄆࡉࢀࡓ࡜࠸࠺࢔ࣥࢣ࣮ࢺ⤖ᯝ
ࢆሗ࿌ࡋ࡚࠸ࡿ㸦Hariparsad et al., 2017㸧ࠋࡲࡓࠊྠሗ࿌࡟࠾࠸࡚ᑐ㇟ศᏊ✀ࡣࠊ㓝⣲ㄏᑟ࡛ホ౯
ᑐ㇟࡜࡞ࡗ࡚࠸ࡿศᏊ✀ࡢ඲࡚ࡢศᏊ✀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 CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࡀㄆࡵࡽࢀࡿ஦౛ࡀሗ࿌ࡉࢀ࡚
࠾ࡾࠊྛ〇⸆௻ᴗࡣin vitroࡢ㓝⣲ㄏᑟࢫࢡ࣮ࣜࢽࣥࢢ࡛⃰ᗘ౫Ꮡⓗ࡞CYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙ
ࣥࡀ་⸆ရೃ⿵໬ྜ≀࡛ㄆࡵࡽࢀࡓሙྜ࡟ࡣࠊᑡ࡞࠸▱ぢ࠿ࡽࡑࡢ࣓࢝ࢽࢬ࣒ࡸ⮫ᗋ࡟࠾ࡅࡿᙳ
㡪ࢆ⪃៖ࡋ࡞ࡅࢀࡤ࡞ࡽ࡞࠸ࡢࡀ⌧≧࡛࠶ࡿࠋࡋࡓࡀࡗ࡚ࠊࡇࢀࡲ࡛ࡢࣄࢺin vivo⮫ᗋ⸆≀┦஫స
⏝ヨ㦂ࡢ⤖ᯝ࡞࡝࠿ࡽࠊCYPࢲ࢘ࣥࣞࢠ࣮ࣗࣞࢩࣙࣥࢆᘬࡁ㉳ࡇࡋ࡚࠸ࡿྍ⬟ᛶࡀ࠶ࡿ஦౛ࢆ㞟
⣙ࡋࠊࡑࢀࢆ᳨ド໬ྜ≀࡜ࡋ࡚in vitro࡛ࡢ࣓࢝ࢽࢬ᳨࣒ドࡸࠊin vivo࡬ࡢእᤄࢆ᳨ドࡋ࡚࠸ࡃࡇ࡜
ࡣ㔜せ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡿࠋ













ᮏ◊✲࡛ࡣࠊCYP1A2ࡢ඾ᆺᇶ㉁࡛࠶ࡿ࢝ࣇ࢙࢖ࣥ࡜ཎⓎᛶ⫹Ồᛶ⫹⟶⅖἞⒪๣࡛࠶ࡿ࢜࣋ࢳ
ࢥ࣮ࣝ㓟㸦Fig. ...

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