藥物開發(fā)和藥物相互作用 | 底物，抑制劑和誘導(dǎo)劑表

菜鳥博士Caesar

FDA發(fā)布 菜鳥博士學(xué)習(xí)

Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers
藥物開發(fā)和藥物相互作用 | 底物，抑制劑和誘導(dǎo)劑表

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• CYP Enzymes CYP 酶

• In vitro 體外培養(yǎng)

• In vitro marker reactions 體外標(biāo)記反應(yīng)

• In vitro selective inhibitors 體外選擇性抑制劑

• In vitro inducers 體外誘導(dǎo)劑

• Clinical index drugs 臨床指標(biāo)藥物

• Clinical index substrates 臨床指標(biāo)基礎(chǔ)

• Clinical index inhibitors 臨床指數(shù)抑制劑

• Clinical index inducers 臨床指數(shù)誘導(dǎo)劑

• Examples of clinical substrates, inhibitors, and inducers 臨床底物、抑制劑和誘導(dǎo)劑的例子

• Clinical substrates 臨床基礎(chǔ)

• Clinical inhibitors 臨床抑制劑

• Clinical inducers 臨床誘導(dǎo)劑

• Transporters 運(yùn)輸工具

• In vitro 體外培養(yǎng)

• In vitro substrates 體外基質(zhì)

• In vitro inhibitors 體外抑制劑

• Examples of clinical substrates, inhibitors and inducers 臨床底物、抑制劑和誘導(dǎo)劑的例子

• Clinical substrates 臨床基礎(chǔ)

• Clinical inhibitors 臨床抑制劑

Table 1-1: Examples of in vitro marker reactions for P450-mediated metabolism (9/26/2016)
表1-1: p450介導(dǎo)的代謝體外標(biāo)記反應(yīng)實(shí)例(9/26/2016)

Enzyme 酶Marker reaction 標(biāo)記反應(yīng)CYP1A2Phenacetin O-deethylation, 7-Ethoxyresorufin-O-deethylation 非那西丁 o 脫乙基，7- 乙氧基間苯二酚 o 脫乙基CYP2B6Efavirenz hydroxylation, Bupropion hydroxylation 依法韋倫的羥基化，安非他酮的羥基化CYP2C8 2c8Paclitaxel 6α-hydroxylation, Amodiaquine N-deethylation 紫杉醇6α 羥基化，阿莫地喹 n- 脫乙基化CYP2C9 2c9S-Warfarin 7-hydroxylation, Diclofenac 4'-hydroxylation S-Warfarin 7- 羥基化，雙氯芬酸4’-羥基化CYP2C19 2c19S-Mephenytoin 4'-hydroxylation S-Mephenytoin 4’-羥基化反應(yīng)CYP2D6Bufuralol 1'-hydroxylation, Dextromethorphan O-demethylation 右美沙芬羥基化，o-去甲基化CYP3A4/5* CYP3A4/5 *Midazolam 1'-hydroxylation, Testosterone 6β-hydroxylation 咪達(dá)唑侖1’-羥基化，睪酮6β-羥基化

* Recommend the use of 2 structurally unrelated CYP3A4/5 substrates for evaluation of in vitro CYP3A4/5 inhibition.
* 建議使用2個(gè)結(jié)構(gòu)不相關(guān)的 CYP3A4/5底物進(jìn)行體外 CYP3A4/5抑制作用的評(píng)估。

Table 1-2: Examples of in vitro selective inhibitors for P450-mediated metabolism (9/26/2016)
表1-2: p450介導(dǎo)的代謝體外選擇性抑制劑的例子(9/26/2016)

Enzyme 酶Inhibitor 抑制劑CYP1A2α-Naphthoflavone, Furafylline* Α- 萘黃酮，呋喃甲酰胺 *CYP2B6** 2b6 * *Sertraline, Phencyclidine*, Thiotepa*, Ticlopidine* 鹽酸舍曲林，苯環(huán)己哌啶，硫代替帕，噻氯匹啶CYP2C8 2c8Montelukast, Quercetin, Phenelzine* 孟魯司特，槲皮素，苯乙嗪 *CYP2C9 2c9Sulfaphenazole, Tienilic acid* 磺胺苯唑，硫尼酸 *CYP2C19** 2c19 * *S-(+)-N-3-benzyl-nirvanol, Nootkatone, Ticlopidine* S-(+)-n-3- 芐基 -nirvanol，Nootkatone，噻氯匹啶 *CYP2D6Quinidine, Paroxetine* 奎尼丁，帕羅西汀 *CYP3A4/5Itraconazole, Ketoconazole, Azamulin*, Troleandomycin*, Verapamil* 伊曲康唑，酮康唑，阿霉素 * ，曲霉素 * ，維拉帕米 *

Most chemical inhibitors are not specific for an individual CYP enzyme. The selectivity and potency of inhibitors should be verified in the same experimental conditions using probe substrates for each CYP enzyme.
大多數(shù)化學(xué)抑制劑不是針對(duì)單個(gè) CYP 酶的。在相同的實(shí)驗(yàn)條件下，應(yīng)使用每種 CYP 酶的探針底物來驗(yàn)證抑制劑的選擇性和效力。
* Time-dependent inhibitors. **No selective inhibitor is available in vitro for CYP2C19- and CYP2B6-mediated metabolisms. The inhibitors listed here can be used together with other information, such as metabolic profiles obtained from single enzyme expression systems.
* 依賴時(shí)間的抑制劑。* * 體外沒有選擇性抑制劑可用于 cyp2c19和 cyp2b6介導(dǎo)的代謝。這里列出的抑制劑可以與其他信息一起使用，例如從單一酶表達(dá)系統(tǒng)獲得的代謝譜。

Table 1-3. Examples of in vitro inducers for P450-mediated metabolism (9/26/2016)
表1-3. p450介導(dǎo)的體外代謝誘導(dǎo)劑的例子(9/26/2016)

Enzyme 酶Inducer* 誘導(dǎo)物 *CYP1A2Omeprazole, Lansoprazole 奧美拉唑，蘭索拉唑CYP2B6Phenobarbital 苯***CYP2C8 2c8Rifampicin 利福平CYP2C9 2c9Rifampicin 利福平CYP2C19 2c19Rifampicin 利福平CYP3A4/5Rifampicin 利福平

Table 2-1: Examples of clinical index substrates for P450-mediated metabolism (for use in index clinical DDI studies) (9/26/2016)
表2-1: p450介導(dǎo)的代謝(用于指數(shù)臨床 DDI 研究)的臨床指數(shù)底物示例(9/26/2016)

Sensitive index substrates unless otherwise noted 敏感的索引基板，除非另有說明CYP1A2caffeine, tizanidine 咖啡因，替扎尼定CYP2B6(a)-CYP2C8 2c8repaglinide 瑞格列奈(b)CYP2C9 2c9tolbutamide 甲苯磺丁脲(c), S-warfarin ，s- 華法林(c)CYP2C19 2c19lansoprazole (c,d), omeprazole 蘭索拉唑(c，d)奧美拉唑CYP2D6desipramine, dextromethorphan, nebivolol 地昔帕明，右美沙芬，奈比沃洛爾CYP3A 細(xì)胞色素 p3amidazolam, triazolam 咪達(dá)唑侖，三唑侖

* Note: Index substrates predictably exhibit exposure increase due to inhibition or induction of a given metabolic pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main clinical DDI guidance document for details. Sensitive index substrates are index drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drug that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.
* 注: 指數(shù)基質(zhì)可預(yù)見地表現(xiàn)出暴露增加由于抑制或誘導(dǎo)給定的代謝途徑，并通常用于前瞻性臨床 DDI 研究。見第四節(jié) a. 2。有關(guān)詳情，請(qǐng)參閱主要臨床 DDI 指引文件。敏感指數(shù)底物是指數(shù)藥物，在臨床 DDI 研究中表明，在給定代謝途徑的強(qiáng)指數(shù)抑制劑的作用下，AUC 增加≥5倍。中度敏感的底物是在臨床 DDI 研究中顯示 AUC ≥2到 < 5倍增加的藥物，并且使用給定代謝途徑的強(qiáng)指數(shù)抑制劑。
This table is prepared to provide examples of clinical sensitive or moderate sensitive index substrates and is not intended to be an exhaustive list. Index substrates listed in this table were selected considering their sensitivity, specificity, safety profiles, and adequate number of reported clinical DDI studies with different in vivo inhibitors (≥ 3 for CYP3A or ≥ 2 for CYP1A2, 2C8, 2C9, 2C19, and 2D6). DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61],?and the list of references is available here.
此表準(zhǔn)備提供臨床敏感或中等敏感指數(shù)基板的例子，并不打算是一個(gè)詳盡的清單。本表中列出的指數(shù)基質(zhì)是根據(jù)其敏感性、特異性、安全性和足夠數(shù)量的已報(bào)道的不同體內(nèi)抑制劑(CYP3A ≥3或 CYP1A2、2C8、2C9、2c19和2d6≥2)的臨床 DDI 研究選擇的。DDI 數(shù)據(jù)是基于對(duì)華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索而收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a) We currently do not have sensitive index substrates for CYP2B6.
(b) Also OATP1B1 substrate.
(c) Moderate sensitive substrates.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.
(a)我們目前沒有 cyp2b6的敏感指數(shù)底物。(b)亦為 oatp1b1底物。(c)中度感應(yīng)強(qiáng)的基質(zhì)。(d) s-蘭索拉唑是 cyp2c19電鏡檢查的敏感底物。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1.
縮寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物-藥物相互作用; EM: 廣泛代謝物; OATP1B1: 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽1b1。

Table 2-2: Examples of clinical index inhibitors for P450-mediated metabolisms (for use in index clinical DDI studies) (9/26/2016)
表2-2: p450介導(dǎo)代謝的臨床指數(shù)抑制劑的例子(用于指數(shù)臨床 DDI 研究)(9/26/2016)

Strong index inhibitors 強(qiáng)指數(shù)抑制劑Moderate index inhibitors 中等指數(shù)抑制劑CYP1A2fluvoxamine 氟伏沙明(a)-CYP2B6(b)--CYP2C8 2c8clopidogrel 氯吡格雷(c), gemfibrozil 吉非羅齊(d)-CYP2C9 2c9-fluconazole 氟康唑(e)CYP2C19 2c19fluvoxamine 氟伏沙明(a)-CYP2D6fluoxetine 氟西汀(f), paroxetine 帕羅西汀mirabegronCYP3A 細(xì)胞色素 p3aclarithromycin 克拉霉素(g), itraconazole ，伊曲康唑(g)erythromycin, fluconazole 紅霉素，氟康唑(e), verapamil 維拉帕米(g)

Note: Index inhibitors predictably inhibit metabolism via a given pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main guidance documents for details. Strong and moderate inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold and ≥2 to <5-fold, respectively.
注意: 指數(shù)抑制劑通過一個(gè)給定的途徑可預(yù)測(cè)地抑制代謝，并且通常用于前瞻性臨床 DDI 研究。見第四節(jié) a. 2。詳情請(qǐng)參閱主要指引文件。強(qiáng)抑制劑和中抑制劑是分別提高給定代謝途徑敏感指數(shù)底物 AUC ≥5倍和≥2 < 5倍的藥物。
This table is prepared to provide examples of clinical index inhibitors and is not intended to be an exhaustive list. Index inhibitors listed in this table were selected based on potency and selectivity of inhibition, safety profiles, and adequate number of reported clinical DDI studies with different in vivo substrates [≥ 3 for CYP3A, ≥ 2 for CYP1A2, 2C9, 2C19, and 2D6, or ≥ 1 for CYP2C8 (strong inhibitors)]. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61)], and the?list of references is available here.
本表準(zhǔn)備提供臨床指數(shù)抑制劑的例子，并不打算是一個(gè)詳盡的清單。本表所列的指數(shù)抑制劑是根據(jù)抑制的效力和選擇性、安全性和足夠數(shù)量的已報(bào)道的臨床 DDI 研究，不同的體內(nèi)底物[ CYP3A ≥3，CYP1A2,2C9,2c19和2d6≥2，或 CYP2C8(強(qiáng)抑制劑)≥1]篩選的。DDI 數(shù)據(jù)是基于對(duì)華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索而收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61] ，參考文獻(xiàn)列表可在此查閱。
(a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A.
(b) We currently do not have index inhibitors for CYP2B6.
(c) Strong inhibitor of CYP2C8, weak inhibitor of CYP2B6, and inhibitor of OATP1B1. The glucoronide metabolite is also an inhibitor for CYP2C8 and OATP1B1.
(d) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3. The glucoronide metabolite is also an inhibitor for CYP2C8 and OATP1B1.
(e) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.
(f) Strong inhibitors of CYP2C19 and CYP2D6. (g) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).
(a) cyp1a2和 cyp2c19的強(qiáng)抑制劑，cyp2d6和 CYP3A 的中度抑制劑。(b)我們目前沒有 cyp2b6的指數(shù)抑制劑。
(c) cyp2c8的強(qiáng)抑制劑、 cyp2b6的弱抑制劑和 oatp1b1的抑制劑。葡萄糖苷類代謝物也是 cyp2c8和 oatp1b1的抑制劑。
(d) cyp2c8強(qiáng)抑制劑和 oatp1b1和 oat3強(qiáng)抑制劑。葡萄糖苷類代謝物也是 cyp2c8和 oatp1b1的抑制劑。
(e) cyp2c19強(qiáng)抑制劑和 CYP2C9、 CYP3A 中度抑制劑。
(f) cyp2c19和 cyp2d6的強(qiáng)抑制劑(g) P-gp 的抑制劑(定義為地高辛的 AUC 增加到≥1.25倍)。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; OATP1B1: organic anion transporting polypeptide 1B1; OAT3: organic anion transporter 3; P-gp: P-glycoprotein.
簡(jiǎn)寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物相互作用; OATP1B1: 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽1b1; OAT3: 有機(jī)陰離子轉(zhuǎn)運(yùn)蛋白3; P-gp: p- 糖蛋白。

Table 2-3: Examples of clinical index inducers for P450-mediated metabolisms (for use in index clinical DDI studies) (9/26/2016)
表2-3: p450介導(dǎo)代謝的臨床指數(shù)誘導(dǎo)劑實(shí)例(用于指數(shù)臨床 DDI 研究)(9/26/2016)

Strong inducers 強(qiáng)大的誘導(dǎo)劑Moderate inducers 適度的誘導(dǎo)劑CYP1A2--CYP2B6-rifampin 利福平(a)CYP2C8 2c8-rifampin 利福平(a)CYP2C9 2c9-rifampin 利福平(a)CYP2C19 2c19rifampin 利福平(a)-CYP3A 細(xì)胞色素 p3aphenytoin 苯妥英(b), rifampin 利福平(a)-

Note: Index inducers predictably induce metabolism via a given pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main guidance documents for details. Strong and moderate index inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80% and ≥50% to <80%, respectively.
注: 指數(shù)誘導(dǎo)劑通過給定的途徑誘導(dǎo)代謝，在前瞻性 DDI 臨床研究中常用。見第四節(jié) a. 2。詳情請(qǐng)參閱主要指引文件。強(qiáng)指數(shù)誘導(dǎo)劑和中等指數(shù)誘導(dǎo)劑分別使給定代謝途徑敏感指數(shù)底物的 AUC 降低≥80% 和≥50% 至 < 80% 。
This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. Index inducers listed in this table were selected based on potency of induction, safety profiles, and number of reported clinical DDI studies with different in vivo substrates (≥ 2 substrates). DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61],?and the list of references is available here.
本表準(zhǔn)備提供臨床指數(shù)誘導(dǎo)物的例子，并不打算是一個(gè)詳盡的清單。本表列出的指數(shù)誘導(dǎo)劑是根據(jù)誘導(dǎo)效力、安全性和已報(bào)道的使用不同體內(nèi)基質(zhì)(≥2個(gè)基質(zhì))進(jìn)行的臨床 DDI 研究數(shù)量選擇的。DDI 數(shù)據(jù)是基于對(duì)華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索而收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a) Strong inducer of CYP1A2, CYP2C19, CYP3A, and moderate inducer of CYP2B6, CYP2C8, CYP2C9.
(b) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
(a) CYP1A2、 CYP2C19、 CYP3A 的強(qiáng)誘導(dǎo)劑和 CYP2B6、 CYP2C8、 cyp2c9的中等誘導(dǎo)劑;。(b) CYP3A 的強(qiáng)誘導(dǎo)劑和 CYP1A2、 cyp2c19的中度誘導(dǎo)劑。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.
縮寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物-藥物相互作用。

Table 3-1: Examples of clinical substrates for P450-mediated metabolism (for concomitant use clinical DDI studies and/or drug labeling) (12/03/2019)
表3-1: p450介導(dǎo)的代謝臨床基質(zhì)的例子(同時(shí)使用臨床 DDI 研究和/或藥物標(biāo)記)(12/03/2019)

Sensitive substrates 敏感的基質(zhì)Moderate sensitive substrates 適度敏感的基質(zhì)CYP1A2alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine 阿洛司瓊，咖啡因，度洛西汀，褪黑激素，拉美丁，塔西美丁，替扎尼定clozapine, pirfenidone, ramosetron, theophylline 氯氮平，吡非尼酮，雷莫司瓊，茶堿CYP2B6bupropion 安非他酮(a)efavirenz 依法韋倫茨(a)CYP2C8 2c8repaglinide 瑞格列奈(b)montelukast, pioglitazone, rosiglitazone 孟魯司特，吡格列酮，羅格列酮CYP2C9 2c9celecoxib 塞來昔布(c)glimepiride, phenytoin, tolbutamide, warfarin 格列美脲，苯妥英，甲苯磺丁脲，華法林CYP2C19 2c19S-mephenytoin, omeprazole S- 美苯妥英，奧美拉唑diazepam, lansoprazole 安定，蘭索拉唑(d), rabeprazole, voriconazole ，雷貝拉唑，伏立康唑CYP2D6atomoxetine, desipramine, dextromethorphan , eliglustat 阿托莫西汀，地昔帕明，右美沙芬，埃利格魯司特(e), nebivolol, nortriptyline, perphenazine, tolterodine, R-venlafaxine )、奈比洛爾、去甲替林、奮乃靜、托特羅定、右文拉法辛encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, trimipramine, S-venlafaxine 恩卡尼，丙咪嗪，美托洛爾，普羅帕酮，心得安，曲馬多，曲米帕明，s- 文拉法辛CYP3A 細(xì)胞色素 p3aalfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir ****，阿凡那非，丁螺環(huán)酮，科尼帕坦，達(dá)非那新，達(dá)魯那韋(f), ebastine, everolimus, ibrutinib, lomitapide, lovastatin 依巴斯汀，依莫莫司，依布魯替尼，洛米他濱，洛伐他汀(g), midazolam, naloxegol, nisoldipine, saquinavir ，咪達(dá)唑侖，納絡(luò)酮，尼索地平，沙奎那韋爾(f), simvastatin 辛伐他汀(g), sirolimus, tacrolimus, tipranavir 西羅莫司，他克莫司，替普那韋(f), triazolam, vardenafil 三唑侖，伐地那非alprazolam, aprepitant, atorvastatin 阿普唑侖，阿普匹坦，阿托伐他汀(c), colchicine, eliglustat 秋水仙堿，eliglustat(e), pimozide, rilpivirine, rivaroxaban, tadalafil 皮莫齊德，利匹韋林，利伐洛沙班，他達(dá)拉非budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir 布地奈德，達(dá)沙替尼，卓尼達(dá)龍，依替普坦，依普列酮，非洛地平，依地那韋(f), lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 盧拉西酮，馬拉維洛克，奎硫平，西地那非，替卡瑞洛，托伐普坦

Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line. Other elimination pathways may also contribute to the elimination of the substrates listed in the table above and should be considered when assessing the drug interaction potential.
注: 敏感底物是指在臨床 DDI 研究中顯示 AUC ≥5倍增長的藥物，并且使用給定代謝途徑的強(qiáng)指數(shù)抑制劑。中度敏感的底物是在臨床 DDI 研究中顯示 AUC ≥2到 < 5倍的藥物，并且使用給定代謝途徑的強(qiáng)指數(shù)抑制劑。在虛線上方顯示了與強(qiáng)指數(shù)抑制劑共同給藥使 AUC 增加≥10倍的 CYP3A 敏感底物。其他消除途徑也可能有助于消除上表所列底物，在評(píng)估藥物相互作用潛力時(shí)應(yīng)予以考慮。
This table is prepared to provide examples of clinical substrates and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].
本表準(zhǔn)備提供臨床基礎(chǔ)的例子，并不打算是一個(gè)詳盡的清單。DDI 數(shù)據(jù)是基于華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索而收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a) Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of other pathway(s).
(b) OATP1B1 substrate.
(c)Listed based on pharmacogenetic studies.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.
(e) Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A.
(f) Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.
(g) Acid form is an OATP1B1 substrate
(a)根據(jù)體內(nèi)誘導(dǎo)研究列出，觀察到的效應(yīng)可能部分歸因于其他途徑的誘導(dǎo)。(b) oatp1b1底物。
(c)根據(jù)藥物遺傳學(xué)研究列出。
(d) s-蘭索拉唑是 cyp2c19電鏡檢查的敏感底物。
(e) cyp2d6的敏感底物和 CYP3A 的中度敏感底物。
(f)通常與強(qiáng)效 CYP3A 抑制劑利托那韋聯(lián)合使用。
(g)酸形式為 oatp1b1底物
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1.
縮寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物-藥物相互作用; EM: 廣泛代謝物; OATP1B1: 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽1b1。

Table 3-2: Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (03/06/2020)
表3-2: 臨床抑制劑的例子 p450介導(dǎo)的代謝(同時(shí)使用臨床 DDI 研究和/或藥物標(biāo)記)(03/06/2020)

Strong inhibitors 強(qiáng)效抑制劑Moderate inhibitors 中度抑制劑Weak inhibitors 弱抑制劑CYP1A2ciprofloxacin, enoxacin, fluvoxamine 環(huán)丙沙星，依諾沙星，氟伏沙明(a)methoxsalen, mexiletine ,oral contraceptives 甲氧沙林，美西律，口服避孕藥acyclovir, allopurinol, cimetidine, peginterferon alpha-2a, piperine, zileuton 阿昔洛韋，別嘌呤醇，西咪替丁，聚乙二醇干擾素 α-2a 胡椒堿，齊留通CYP2B6--clopidogrel 氯吡格雷(b), tenofovir, ticlopidine ，替諾福韋，噻氯匹定(c), voriconazole 伏立康唑(voriconazole)(d)CYP2C8 2c8gemfibrozil 吉非羅齊(e)clopidogrel 氯吡格雷(b), deferasirox, teriflunomide 地拉羅司，特利氟米特trimethoprim 甲氧芐啶CYP2C9 2c9-amiodarone, fluconazole 胺碘酮，氟康唑(f), miconazole, piperine ，咪康唑，胡椒堿diosmin, disulfiram, fluvastatin, fluvoxamine 地奧司明，雙硫侖，氟伐他汀，氟伏沙明(a), voriconazole 伏立康唑(voriconazole)CYP2C19 2c19fluconazole 氟康唑(f), fluoxetine 氟西汀(g), fluvoxamine 氟伏沙明(a), ticlopidine ，噻氯匹定felbamate 聯(lián)苯胺酸鹽omeprazole, voriconazole 奧美拉唑，伏立康唑CYP2D6bupropion, fluoxetine 安非他酮，氟西汀(g), paroxetine, quinidine 帕羅西汀，奎尼丁(h), terbinafine 特比奈芬abiraterone, cinacalcet, duloxetine, lorcaserin, mirabegron 阿比特龍，西那卡塞，度洛西汀，氯卡色林，米拉貝根amiodarone, celecoxib, cimetidine, clobazam, cobicistat, escitalopram, fluvoxamine 胺碘酮，塞來昔布，西咪替丁，氯巴占，復(fù)方西酞普蘭，氟伏沙明(a), labetalol, ritonavir 拉貝洛爾，利托那韋(h,i,j) (h，i，j), sertraline, vemurafenib 舍曲林，維莫拉非尼CYP3A4boceprevir, cobicistat Boceprevir copicstat(h), danoprevir and ritonavir 丹諾普瑞和利托那韋(j), elvitegravir and ritonavir ，elvitegraivr 和 ritonavir(j), grapefruit juice 葡萄柚汁(k), indinavir and ritonavir Indinavir 和 ritonavir(j), itraconazole ，伊曲康唑(h), ketoconazole, lopinavir and ritonavir )、酮康唑(酮康唑)、洛匹那韋(lopinavir)、利托那韋(ritonavir)(h,j) (h，j), paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 、 paritaprevir 和 ritonavir 及(ombitasvir 和/或 dasabuvir)(j), posaconazole, ritonavir(h,j), saquinavir and ritonavir 目的研究利托那韋(ritonavir，h，j)、沙奎那韋(saquinavir)和利托那韋(ritonavir)的抗菌作用(h,j) (h，j), telaprevir ，telapreir(h), tipranavir and ritonavir 提普那韋和利托那韋(h,j) (h，j), telithromycin, troleandomycin, voriconazole )、特利紅霉素、曲列安霉素、伏立康唑aprepitant, ciprofloxacin, conivaptan 安眠藥，環(huán)丙沙星，尼伐普坦(l), crizotinib, cyclosporine, diltiazem 目的: 研究環(huán)孢霉素(cyclosporine)、克唑替尼(crizotinib)、地爾硫卓(diltiazem)、環(huán)孢霉素(cyclosporine)、地爾硫(m), dronedarone 我是 dronedarone(h), erythromycin, fluconazole ，紅霉素，氟康唑(f), fluvoxamine 氟伏沙明(a), imatinib, tofisopam, verapamil 伊馬替尼，托非索泮，維拉帕米(h)chlorzoxazone, cilostazol, cimetidine, clotrimazole, fosaprepitant, istradefylline, ivacaftor 氯唑沙宗，西洛他唑，西咪替丁，克霉唑，福沙匹坦，依斯特拉德菲林，依伐他汀(h), lomitapide, ranitidine, ranolazine 洛米他濱，雷尼替丁，雷諾嗪(h), ticagrelor 地卡格雷勒(h)clarithromycin 克拉霉素(h), idelalisib, nefazodone, nelfinavir 伊德拉西布，奈法唑酮，奈非那韋(h)--

Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively. Strong inhibitors of CYP3A causing ≥10-fold increase in AUC of sensitive index substrate(s) are shown above the dashed line.
注意: 強(qiáng)、中、弱抑制劑分別是增加給定代謝途徑敏感指數(shù)底物 AUC ≥5倍，≥2 ~ < 5倍，≥1.25 ~ < 2倍的藥物。在虛線上方顯示強(qiáng)烈的 CYP3A 抑制劑，使敏感指數(shù)底物的 AUC 增加≥10倍。
This table is prepared to provide examples of clinical inhibitors and is not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].
本表準(zhǔn)備提供臨床抑制劑的例子，并不打算是一個(gè)詳盡的清單。DDI 數(shù)據(jù)是在華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索基礎(chǔ)上收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a) Strong inhibitor of CYP1A2 and CYP2C19. Moderate inhibitor of CYP3A and Weak inhibitor of CYP2D6.
(b) Moderate inhibitor of CYP2C8 and weak inhibitor of CYP2B6.
(c) Strong inhibitor of CYP2C19 and weak inhibitor of CYP2B6.
(d) Strong inhibitor of CYP2C19 and CYP3A, and weak inhibitor of CYP2B6.
(e) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3.
(f) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. (g) Strong inhibitors of CYP2C19 and CYP2D6.
(h) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).
(i) Strong inhibitors of CYP3A and weak inhibitor of CYP2D6.
(j) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities.
(k) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).
(l) The classification is based on studies conducted with intravenously administered conivaptan.
(m) Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 5-fold.
(a) cyp1a2和 cyp2c19的強(qiáng)抑制劑。CYP3A 的中度抑制劑和 cyp2d6的弱抑制劑。(b) cyp2c8的中度抑制劑和 cyp2b6的弱抑制劑。
(c) cyp2c19強(qiáng)抑制劑和 cyp2b6弱抑制劑。
(d) cyp2c19和 CYP3A 的強(qiáng)抑制劑和 cyp2b6的弱抑制劑。
(e) cyp2c8的強(qiáng)抑制劑和 oatp1b1和 oat3的強(qiáng)抑制劑。
(f) cyp2c19的強(qiáng)抑制劑和 CYP2C9、 CYP3A 的中度抑制劑;。
P-gp 抑制劑(定義為地高辛 AUC 增加到≥1.25倍)。
(i) CYP3A 的強(qiáng)抑制劑和 cyp2d6的弱抑制劑。
(j)利托那韋在臨床上通常與其他抗 hiv 或抗 hcv 藥物聯(lián)合使用。在推斷單獨(dú)使用利托那韋對(duì)聯(lián)合方案對(duì) CYP3A 活性的影響時(shí)應(yīng)該注意。
(k)葡萄柚汁的作用因品牌不同而有很大差異，并且與濃度、劑量和制劑有關(guān)。研究顯示，當(dāng)使用某種制劑(例如高劑量、雙倍強(qiáng)度)時(shí)，它可被歸類為「強(qiáng)效 CYP3A 抑制劑」 ; 當(dāng)使用另一種制劑(例如低劑量、單倍強(qiáng)度)時(shí)，它可被歸類為「中等程度的 CYP3A 抑制劑」。
(l)分類是根據(jù)靜脈注射 conivaptan 進(jìn)行的研究進(jìn)行的。
(m)地爾硫卓使某些敏感 CYP3A 底物(如丁螺環(huán)酮)的 AUC 增加5倍以上。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; HIV: human immunodeficiency virus; HCV: hepatitis C virus; OATP1B1: organic anion transporting polypeptide 1B1; OAT3: organic anion transporter 3; P-gp: P-glycoprotein.
簡(jiǎn)寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物相互作用; HIV: 人類免疫缺陷病毒; HCV: 丙型肝炎病毒; OATP1B1: 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽1b1; OAT3: 有機(jī)陰離子轉(zhuǎn)運(yùn)蛋白3; P-gp: p-糖蛋白。

Table 3-3: Examples of clinical inducers for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (12/03/2019)
表3-3: 臨床誘導(dǎo)劑 p450介導(dǎo)的代謝(同時(shí)使用臨床 DDI 研究和/或藥物標(biāo)記)的例子(12/03/2019)

Strong inducers 強(qiáng)大的誘導(dǎo)劑Moderate inducers 適度的誘導(dǎo)劑Weak inducers 弱誘導(dǎo)劑CYP1A2phenytoin 苯妥英(a) rifampin(b), ritonavir 利福平(b)利托那韋(c,d) (c，d), smoking, teriflunomide ，吸煙，特利氟米特-CYP2B6carbamazepine 卡馬西平(e)efavirenz 依法韋倫茨(e), rifampin 利福平(a)nevirapine, ritonavir 奈韋拉平，利托那韋(c, d) (c，d)CYP2C8 2c8-rifampin 利福平(a)-CYP2C9 2c9-enzalutamide 恩扎魯他胺(g), rifampin 利福平(a)apalutamide, aprepitant, carbamazepine 阿帕魯丁胺，阿帕匹坦，卡馬西平(e), ritonavir 利托那韋(c, d) (c，d)CYP2C19 2c19rifampin 利福平(a)apalutamide, efavirenz 阿帕魯他胺，依法韋倫茲(e,f) (e，f), enzalutamide Enzalutamide(g), phenytoin 苯妥英鈉(b)ritonavir 利托那韋(c, d) (c，d)CYP3A 細(xì)胞色素 p3aapalutamide, carbamazepine 阿帕魯胺，卡馬西平(e), enzalutamide Enzalutamide(g), mitotane, phenytoin 米托坦，苯妥英(b), rifampin 利福平(a), St. John’s wort 圣約翰草(h)bosentan, efavirenz Bosentan，efavirenz(f), etravirine, phenobarbital, primidone 依曲韋林，苯***，普利米酮armodafinil, modafinil 阿莫達(dá)非尼，莫達(dá)非尼(i), rufinamide ，rufinamide

Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.
注: 強(qiáng)誘導(dǎo)劑、中誘導(dǎo)劑和弱誘導(dǎo)劑分別使給定代謝途徑敏感指數(shù)基質(zhì)的 AUC 降低≥80% ，≥50% 至 < 80% ，≥20% 至 < 50% 。
This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].
本表準(zhǔn)備提供臨床指數(shù)誘導(dǎo)物的例子，并不打算是一個(gè)詳盡的清單。DDI 數(shù)據(jù)是在華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索基礎(chǔ)上收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
(b) Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9.
(c) Moderate inducer of CYP1A2 with dose of 800 mg/day ritonavir (not with other anti-HIV drugs). Effect on CYP1A2 at lower doses of ritonavir is unknown.
(d) Weak inducer of CYP2B6, CYP2C9, and CYP2C19. Classification is based on studies conducted with ritonavir itself (not with other anti-HIV drugs) at doses of 100-200 mg/day, although larger effects have been reported in literature for high doses of ritonavir.
(e) Strong inducer of CYP2B6, CYP3A, and weak inducer of CYP2C9.
(f) Moderate inducer of CYP2B6, CYP2C19 and CYP3A.
(g) Strong inducer of CYP3A and moderate inducer of CYP2C9, and CYP2C19.
(h) The effect of St. John’s wort varies widely and is preparation-dependent.
(i) Based on effect of 200 mg/day modafinil. A higher dose (400 mg/day) modafinil had larger induction effect on CYP3A.
(a) CYP3A 的強(qiáng)誘導(dǎo)劑和 CYP1A2、 cyp2c19的中度誘導(dǎo)劑。(b) CYP2C19、 CYP3A 的強(qiáng)誘導(dǎo)劑和 CYP1A2、 CYP2B6、 CYP2C8、 cyp2c9的中度誘導(dǎo)劑。
(c)中等劑量的 cyp1a2誘導(dǎo)劑，劑量為800毫克/天利托那韋(不與其他抗艾滋病毒藥物合用)。低劑量利托那韋對(duì) cyp1a2的影響尚不清楚。
(d) CYP2B6、 cyp2c9和 cyp2c19的弱誘導(dǎo)物。分類依據(jù)的是利托那韋本身(不與其他抗艾滋病毒藥物一起)在100-200毫克/天劑量下進(jìn)行的研究，盡管文獻(xiàn)報(bào)道高劑量利托那韋的影響更大。
(e) CYP2B6、 CYP3A 的強(qiáng)誘導(dǎo)劑和 cyp2c9的弱誘導(dǎo)劑。
(f) CYP2B6、 cyp2c19和 CYP3A 的中度誘導(dǎo)物。
(g) CYP3A 的強(qiáng)誘導(dǎo)劑和 cyp2c9和 cyp2c19的中度誘導(dǎo)劑。
(h)圣約翰草的作用差別很大，并且取決于制劑。
(i)200mg/d 的莫達(dá)非尼對(duì) CYP3A 的誘導(dǎo)作用較大，400mg/d 的莫達(dá)非尼對(duì) CYP3A 的誘導(dǎo)作用較大;。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.
縮寫: AUC: 濃度-時(shí)間曲線下面積; CYP: 細(xì)胞色素 P450; DDI: 藥物-藥物相互作用。

Table 4-1: Examples of in vitro substrates for transporters (9/26/2016)
表4-1: 轉(zhuǎn)運(yùn)蛋白體外基質(zhì)的例子(9/26/2016)

Transporter 運(yùn)輸機(jī)Gene 基因Substrate 基質(zhì)P-gpABCB1Digoxin 地高辛(a)Fexofenadine 非索非那定(b,c,d) (b，c，d)Loperamide 洛哌丁胺Quinidine 奎尼丁Talinolol 他林洛爾(c)Vinblastine 長春堿(c)BCRP 英國氣候變化研究會(huì)ABCG2 22-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) 2- 氨基 -1- 甲基 -6- 苯基咪唑[4,5-b ]吡啶(PhIP)(c,e) (c，e)Coumestrol 女名女子名Daidzein 大豆苷元Dantrolene 女名女子名Estrone-3-sulfate 雌酮 -3- 硫酸酯(b,f) (b，f)Genistein 染料木黃酮Prazosin 哌唑嗪(e)Sulfasalazine 柳氮磺吡啶OATP1B1, 1b1,OATP1B3 1b3SLCO1B1,SLCO1B3 1b3Cholecystokinin octapeptide(CCK-8) (g) 八肽膽囊收縮素(CCK-8)(克)Estradiol-17β-glucuronide 雌二醇 -17β- 葡萄糖醛酸苷(h)Estrone-3-sulfate 雌酮 -3- 硫酸酯(i)Pitavastatin 皮他伐他汀(c,e,f,j) (c e f j)Pravastatin 普伐他汀(c,f,k) (c f k)Telmisartan 替米沙坦(l)Rosuvastatin 瑞舒伐他汀(c,f,j,k) (c f j k)OAT1SLC22A6Adefovir 阿德福韋p-aminohippurate - 氨基馬尿酸鹽Cidofovir 西多福韋Tenofovir 替諾福韋OAT3SLC22A8Benzylpenicillin 青霉素(b)Estrone-3-sulfate 雌酮 -3- 硫酸酯(j,m) (j，m)Methotrexate 甲氨蝶呤(b,c,j,n) (b c j n)Pravastatin 普伐他汀(b,c) (b，c)MATE1, MATE-2K MATE1，MATE-2KSLC47A1, SLC47A2 47a1，SLC47A2Metformin 二甲雙胍(o)1-methyl-4-phenylpyridinium (MPP+) 美國 MPP+ 協(xié)會(huì)(o)Tetraethylammonium (TEA) 四乙基銨(TEA)(o)OCT2SLC22A2Metformin 二甲雙胍(o)1-methyl-4-phenylpyridinium (MPP+) 美國 MPP+ 協(xié)會(huì)(o)Tetraethylammonium (TEA) 四乙基銨(TEA)(o)

Note:
(a) Also a substrate of OATP1B3.
(b) Also a substrate of OATPs.
(c) Also a substrate of MRP2.
(d) Also a substrate of MRP3.
(e) Also a substrate of P-gp.
(f) Also a substrate of NTCP.
(g) Selective substrate of OATP1B3 (vs. OATP1B1).
(h) The Ki value is estimated to be lower in inhibition studies. This substance has appropriate characteristics of a marker drug.
(i) Selective substrate of OATP1B1 (vs. OATP1B3). It is reported that the estimated Ki value in inhibition studies tends to be lower.
(j) Also a substrate of BCRP.
(k) Also a substrate of OAT3.
(l) Selective substrate of OATP1B3 (vs. OATP1B1). Addition of albumin to the study system should be considered to decrease the effects of nonspecific absorption.
(m) Also a substrate of OATP1B1.
(n) Also a substrate of OAT1.
(o) Substrate of OCTs and MATEs.
注: (a)也是 oatp1b3的底物。
(b)也是燕麥片的基質(zhì)。
(c)亦是 mrp2的底物。
(d)亦是 mrp3的底物。
(e)也是 P-gp 的基質(zhì)。
(f)也是 NTCP 的基底。
(g) oatp1b3的選擇性底物(vs. OATP1B1)。
(h)在抑制研究中估計(jì) Ki 值較低。這種物質(zhì)具有標(biāo)記藥物的特征。
(i) oatp1b1的選擇性底物(vs. OATP1B3)。據(jù)報(bào)道，在抑制研究中的估計(jì) Ki 值往往偏低。
(j)也是 BCRP 的底物。
(k)也是 oat3的底物。
(l) oatp1b3的選擇性底物(vs. OATP1B1)。在研究系統(tǒng)中加入白蛋白可以減少非特異性吸收的影響。
(m)也是 oatp1b1的底物。
(n)也是 oat1的底物。
(o) OCTs 和 MATEs 的基底。
This table is prepared to provide examples of in vitro substrates for various transporters and not intended to be an exhaustive list.
本表準(zhǔn)備提供各種轉(zhuǎn)運(yùn)蛋白的體外基質(zhì)實(shí)例，并非詳盡無遺的清單。

Table 4-2: Examples of in vitro inhibitors for transporters (9/26/2016)
表4-2: 轉(zhuǎn)運(yùn)蛋白體外抑制劑的例子(9/26/2016)

Transporter 運(yùn)輸機(jī)Gene 基因Inhibitor 抑制劑P-gpABCB1Cyclosporine 環(huán)孢霉素(a)Elacridar (GF120918)(b)Ketoconazole 酮康唑(c)Quinidine 奎尼丁(d)Reserpine 利血平(e)Ritonavir 利托那韋(f)Tacrolimus 他克莫司(f)Valspodar (PSC833)(e)Verapamil 維拉帕米(d)Zosuquidar (LY335979)BCRP 英國氣候變化研究會(huì)ABCG2 2Elacridar (GF120918)(g)Fumitremorgin C 深圳市福美瑞金科技有限公司Ko134Ko143Novobiocin 新生霉素Sulfasalazine 柳氮磺吡啶OATP1B1, 1b1,OATP1B3 1b3SLCO1B1,SLCO1B3 1b3Cyclosporine 環(huán)孢霉素(c,e,g,h) (c e g h)Estradiol-17β-glucuronide 雌二醇 -17β- 葡萄糖醛酸苷(b,e) (b，e)Estrone-3-sulfate 雌酮 -3- 硫酸酯(b,c) (b，c)Rifampicin 利福平Rifamycin SV 利福霉素 SVOAT1, OAT3 1，OAT3SLC22A6, SLC22A8 22a6，SLC22A8Benzylpenicillin 青霉素Probenecid 丙磺舒(f)MATE1, MATE-2K MATE1，MATE-2KSLC47A1, SLC47A2 47a1，SLC47A2Cimetidine 西咪替丁(d,i) (d，i)Pyrimethamine 乙胺嘧啶OCT2SLC22A2Cimetidine 西咪替丁(h)

Note:
(a)Inhibitor of MRP2, BCRP, NTCP and OATPs.
(b) Also an inhibitor of BCRP.
(c) Also an inhibitor of NTCP.
(d) Also an inhibitor of OCTs.
(e) Also an inhibitor of MRP2.
(f) Also an inhibitor of OATPs.
(g) Also an inhibitor of P-gp.
(h) Preincubation with inhibitors prior to inhibition studies causes a decrease of the Ki value.
(i) Also an inhibitor of OAT3.
注: (a) MRP2、 BCRP、 NTCP 和 oatp 的抑制劑。
(b)也是 BCRP 的抑制劑。
(c)也是 NTCP 的抑制劑。
(d)也是 OCTs 的抑制劑。
(e)亦為 mrp2的抑制劑。
(f)亦是一種燕麥蛋白抑制劑。
(g)也是 P-gp 的抑制劑。
(h)在抑制研究之前用抑制劑進(jìn)行預(yù)培養(yǎng)會(huì)導(dǎo)致 Ki 值下降。
(i)亦為 oat3的抑制劑。
This table is prepared to provide examples of in vitro inhibitors for various transporters and not intended to be an exhaustive list.
本表準(zhǔn)備提供各種轉(zhuǎn)運(yùn)蛋白體外抑制劑的實(shí)例，并非詳盡無遺的清單。

Table 5-1: Examples of clinical substrates for transporters (for use in clinical DDI studies and/or drug labeling) (12/03/2019)
表5-1: 轉(zhuǎn)運(yùn)蛋白臨床基質(zhì)(用于臨床 DDI 研究和/或藥物標(biāo)簽)的例子(12/03/2019)

Transporter 運(yùn)輸機(jī)Gene 基因Substrate 基質(zhì)P-gpABCB1Dabigatran etexilate, digoxin, fexofenadine 達(dá)比加群依替西酯，地高辛，非索非那定(e)BCRP 英國氣候變化研究會(huì)ABCG2 2rosuvastatin, sulfasalazine 瑞舒伐他汀，柳氮磺吡啶OATP1B1 1b1OATP1B3 1b3SLCO1B1,SLCO1B3 1b3asunaprevir, atorvastatin, bosentan, danoprevir, docetaxel 阿蘇那普利，阿托伐他汀，波生坦，丹諾普利，多西他賽(a), fexofenadine ，非索非那定(e), glyburide, nateglinide, paclitaxel, pitavastatin 格列本脲，那格列奈，紫杉醇，匹他伐他汀(b), pravastatin, repaglinide, rosuvastatin 普伐他汀，瑞格列奈，瑞舒伐他汀(b), simvastatin acid 辛伐他汀酸OAT1OAT3 燕麥3SLC22A6, 22a6,SLC22A8adefovir 阿德福韋(c), cefaclor, ceftizoxime, famotidine 頭孢克洛，頭孢唑肟，法莫替丁(d), furosemide, ganciclovir 速尿，更昔洛韋(c), methotrexate, oseltamivir carboxylate ，甲氨蝶呤，奧司他韋羧酸鹽(d), penicillin G ，青霉素 g(d)MATE1, 1,MATE-2K, OCT2 MATE-2K，OCT2SLC47A1, SLC47A2, SLC22A2 47a1，SLC47A2，SLC22A2metformin 二甲雙胍

Note:
Criteria for selecting clinical substrates are as follows:
注: 選擇臨床基質(zhì)的標(biāo)準(zhǔn)如下:

• P-gp: (1) AUC fold-increase≥2 with verapamil or quinidine co-administration and (2) in vitro transport by P-gp expression systems, but not extensively metabolized. P-gp: (1)與維拉帕米或奎尼丁聯(lián)合應(yīng)用時(shí) AUC 增高≥2，(2) P-gp 表達(dá)系統(tǒng)體外轉(zhuǎn)運(yùn)，但未見廣泛代謝

• BCRP: (1) AUC fold-increase≥2 with pharmacogenetic alteration of ABCG2 (421C>A) and (2) in vitro transport by BCRP expression systems. BCRP: (1) AUC 倍增≥2，ABCG2(421C > a)的藥物遺傳學(xué)改變和(2) BCRP 表達(dá)系統(tǒng)的體外轉(zhuǎn)運(yùn)

• OATP1B1/OATP1B3: (1) AUC fold-increase≥2 with rifampin (single dose) or cyclosporine A co-administration, or pharmacogenetic alteration of SLCO1B1 (521T>C) and (2) in vitro transport by OATP1B1 or OATP1B3 expression systems. OATP1B1/OATP1B3: (1) AUC 倍增≥2與利福平(單劑量)或環(huán)孢素 a 共同給藥，或藥物遺傳學(xué)改變 SLCO1B1(521T > c)和(2) oatp1b1或 oatp1b3表達(dá)系統(tǒng)的體外轉(zhuǎn)運(yùn)

• OAT1/OAT3: (1) AUC fold-increase≥1.5 with probenecid co-administration, (2) fraction excreted unchanged into urine as an unchanged drug ≥ 0.5, and (3) in vitro transport by OAT1 or OAT3 expression systems. OAT1/OAT3: (1)丙磺舒聯(lián)合給藥后 AUC 倍增≥1.5，(2)尿液中未改變的藥物排出尿液≥0.5，(3) oat1或 oat3表達(dá)系統(tǒng)體外轉(zhuǎn)運(yùn)

• OCT2/MATE: Well-established substrate of cationic transport system (metformin). OCT2/MATE: 陽離子傳遞體系(二甲雙胍)的良好底物

This table is prepared to provide examples of clinical substrates for various transporters and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].
本表提供了各種轉(zhuǎn)運(yùn)蛋白的臨床基質(zhì)的例子，并非詳盡無遺的清單。DDI 數(shù)據(jù)是在華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索基礎(chǔ)上收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a)In vitro data suggested higher contribution of OATP1B3 than OATP1B1.
(b)In vitro and pharmacogenetic data suggested higher contribution of OATP1B1 than OATP1B3.
(c)In vitro data suggested higher contribution of OAT1 than OAT3.
(d)in vitro data suggested higher contribution of OAT3 than OAT1.
(e) Fexofenadine is a substrate for both P-gp and OATP1B.
(a)體外數(shù)據(jù)顯示 oatp1b3比 oatp1b1有更高的貢獻(xiàn)。體外和藥物遺傳學(xué)數(shù)據(jù)顯示 oatp1b1的貢獻(xiàn)率高于 OATP1B3。(c)體外數(shù)據(jù)顯示 oat1比 oat3有更高的貢獻(xiàn)。(d)體外數(shù)據(jù)顯示 oat3的含量較 oat1高。(e)非索非那定是 P-gp 和 OATP1B 的底物。
Abbreviations:
AUC: area under the plasma concentration-time curve.
縮寫: AUC: 血漿濃度-時(shí)間曲線下面積。

Table 5-2: Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug labeling) (9/26/2016)
表5-2: 轉(zhuǎn)運(yùn)蛋白臨床抑制劑的例子(用于臨床 DDI 研究和藥物標(biāo)記)(9/26/2016)

Transporter 運(yùn)輸機(jī)Gene 基因Inhibitor 抑制劑P-gp(a)ABCB1amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil 胺碘酮、卡維地洛、克拉霉素、德羅尼達(dá)羅、伊曲康唑、拉帕替尼、洛匹那韋、利托那韋、普羅帕酮、奎尼丁、雷諾嗪、利托那韋、替拉帕那韋、利托那韋、替拉帕那韋BCRP 英國氣候變化研究會(huì)ABCG2 2curcumin, cyclosporine A, eltrombopag 姜黃素，環(huán)孢素 a，艾特羅布帕OATP1B1, OATP1B3 1b1，OATP1B3SLCO1B1, SLCO1B3 1b1，SLCO1B3atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin (single dose), simeprevir 阿扎那韋和利托那韋，克拉霉素，環(huán)孢霉素，紅霉素，吉非羅齊，洛匹那韋和利托那韋，利福平(單劑量) ，西梅普韋韋OAT1, OAT3 1，OAT3SLC22A6, SLC22A8 22a6，SLC22A8p-aminohippuric acid (PAH) 對(duì)氨基馬尿酸(PAH)(b), probenecid, teriflunomide ，丙磺舒，特利氟米特MATE1, MATE2-K MATE1，MATE2-KSLC47A1, SLC47A2 47a1，SLC47A2cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, vandetanib 西咪替丁，杜魯替拉韋，異惡康唑，雷諾嗪，甲氧芐啶，萬德他尼

Note:
Criteria for selecting in vivo inhibitors are as follows:
注: 選擇體內(nèi)抑制劑的標(biāo)準(zhǔn)如下:

• P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor. P-gp: (1)地高辛≥2與體外抑制劑聯(lián)合應(yīng)用時(shí) AUC 倍增

• BCRP: (1) AUC fold-increase of sulfasalazine ≥1.5 with co-administration and (2) in vitro inhibitor. Cyclosporine A and eltrombopag were also included, although the available DDI information was with rosuvastatin, where inhibition of both BCRP and OATPs may have contributed to the observed interaction. BCRP: (1)與鹽酸柳氮磺吡啶合用時(shí)，體外抗腫瘤作用明顯增強(qiáng)(2)。環(huán)孢素 a 和 eltrombpag 也包括在內(nèi)，雖然可用的 DDI 信息是與瑞舒伐他汀，其中 BCRP 和 oatp 的抑制可能有助于觀察到的相互作用

• OATP1B1/OATP1B3: (1) AUC fold-increase ≥2 for at least one of clinical substrates in Table 2-3 with co-administration and (2) in vitro inhibitor. OATP1B1/OATP1B3: (1) AUC 倍增≥2至少一個(gè)臨床底物在表2-3與聯(lián)合給藥和(2)體外抑制劑

• OAT1/OAT3: (1) AUC fold-increase ≥1.5 for at least one of clinical substrates in Table 2-3 with co-administration and (2) in vitro inhibitor.<. i=""> OAT1/OAT3: (1) AUC 倍增≥1.5至少有一個(gè)臨床底物在表2-3與聯(lián)合給藥和(2)體外抑制劑。<.我 =””>

• OCT2/MATE: (1) AUC fold-increase of metformin ≥ 1.5 with co-administration and (2) in vitro inhibitor. OCT2/MATE: (1)聯(lián)合給藥和體外抑制劑使二甲雙胍≥1.5的 AUC 倍增

This table is prepared to provide examples of clinical inhibitors for various transporters and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].
本表準(zhǔn)備提供各種轉(zhuǎn)運(yùn)蛋白的臨床抑制劑的例子，并非詳盡無遺的清單。DDI 數(shù)據(jù)是在華盛頓大學(xué)代謝與運(yùn)輸藥物相互作用數(shù)據(jù)庫的搜索基礎(chǔ)上收集的[ Hachad et al. (2010) ，Hum Genomics，5(1) : 61]。
(a)Most of P-gp inhibitors also inhibit CYP3A. (b)In vivo data suggested specific inhibition of OAT1.
(a)大多數(shù) P-gp 抑制劑也抑制 CYP3A。(b)體內(nèi)數(shù)據(jù)表明 oat1具有特異性抑制作用。
Abbreviations:
AUC: area under the plasma concentration-time curve.
縮寫: AUC: 血漿濃度-時(shí)間曲線下面積。
References
參考資料
Ministry of Health, Labour and Welfare (MHLW), Japan (2014). Drug interaction guideline for drug development and labeling recommendations (Draft, in Japanese)
日本厚生勞動(dòng)省(厚生勞動(dòng)省)(2014年)。藥物相互作用指南藥物開發(fā)和標(biāo)簽建議(草案，日文)
European Medicines Agency (2013). Guideline on the Investigation of Drug Interactions.
歐洲藥物管理局藥物相互作用研究指南(2013)。