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药物开发和药物相互作用 | 底物,抑制剂和诱导剂表

2022-06-22 17:52 作者:菜鸟博士_杂货铺  | 我要投稿

药物开发和药物相互作用 | 底物,抑制剂和诱导剂表

菜鸟博士Caesar

FDA发布 菜鸟博士学习

Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers
药物开发和药物相互作用 | 底物,抑制剂和诱导剂表

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  • CYP Enzymes CYP 酶

    • In vitro 体外培养

      • In vitro marker reactions 体外标记反应

      • In vitro selective inhibitors 体外选择性抑制剂

      • In vitro inducers 体外诱导剂


  • Clinical index drugs 临床指标药物

    • Clinical index substrates 临床指标基础

    • Clinical index inhibitors 临床指数抑制剂

    • Clinical index inducers 临床指数诱导剂


  • Examples of clinical substrates, inhibitors, and inducers 临床底物、抑制剂和诱导剂的例子

    • Clinical substrates 临床基础

    • Clinical inhibitors 临床抑制剂

    • Clinical inducers 临床诱导剂



  • Transporters 运输工具

    • In vitro 体外培养

      • In vitro substrates 体外基质

      • In vitro inhibitors 体外抑制剂


  • Examples of clinical substrates, inhibitors and inducers 临床底物、抑制剂和诱导剂的例子

    • Clinical substrates 临床基础

    • Clinical inhibitors 临床抑制剂



Table 1-1: Examples of in vitro marker reactions for P450-mediated metabolism (9/26/2016)
表1-1: p450介导的代谢体外标记反应实例(9/26/2016)

Enzyme 酶Marker reaction 标记反应CYP1A2Phenacetin O-deethylation, 7-Ethoxyresorufin-O-deethylation 非那西丁 o 脱乙基,7- 乙氧基间苯二酚 o 脱乙基CYP2B6Efavirenz hydroxylation, Bupropion hydroxylation 依法韦伦的羟基化,安非他酮的羟基化CYP2C8 2c8Paclitaxel 6α-hydroxylation, Amodiaquine N-deethylation 紫杉醇6α 羟基化,阿莫地喹 n- 脱乙基化CYP2C9 2c9S-Warfarin 7-hydroxylation, Diclofenac 4'-hydroxylation S-Warfarin 7- 羟基化,双氯芬酸4’-羟基化CYP2C19 2c19S-Mephenytoin 4'-hydroxylation S-Mephenytoin 4’-羟基化反应CYP2D6Bufuralol 1'-hydroxylation, Dextromethorphan O-demethylation 右美沙芬羟基化,o-去甲基化CYP3A4/5* CYP3A4/5 *Midazolam 1'-hydroxylation, Testosterone 6β-hydroxylation 咪达唑仑1’-羟基化,睾酮6β-羟基化


* Recommend the use of 2 structurally unrelated CYP3A4/5 substrates for evaluation of in vitro CYP3A4/5 inhibition.
* 建议使用2个结构不相关的 CYP3A4/5底物进行体外 CYP3A4/5抑制作用的评估。

Table 1-2: Examples of in vitro selective inhibitors for P450-mediated metabolism (9/26/2016)
表1-2: p450介导的代谢体外选择性抑制剂的例子(9/26/2016)

Enzyme 酶Inhibitor 抑制剂CYP1A2α-Naphthoflavone, Furafylline* Α- 萘黄酮,呋喃甲酰胺 *CYP2B6** 2b6 * *Sertraline, Phencyclidine*, Thiotepa*, Ticlopidine* 盐酸舍曲林,苯环己哌啶,硫代替帕,噻氯匹啶CYP2C8 2c8Montelukast, Quercetin, Phenelzine* 孟鲁司特,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- 苄基 -nirvanol,Nootkatone,噻氯匹啶 *CYP2D6Quinidine, Paroxetine* 奎尼丁,帕罗西汀 *CYP3A4/5Itraconazole, Ketoconazole, Azamulin*, Troleandomycin*, Verapamil* 伊曲康唑,酮康唑,阿霉素 * ,曲霉素 * ,维拉帕米 *


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.
大多数化学抑制剂不是针对单个 CYP 酶的。在相同的实验条件下,应使用每种 CYP 酶的探针底物来验证抑制剂的选择性和效力。
* 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.
* 依赖时间的抑制剂。* * 体外没有选择性抑制剂可用于 cyp2c19和 cyp2b6介导的代谢。这里列出的抑制剂可以与其他信息一起使用,例如从单一酶表达系统获得的代谢谱。

Table 1-3. Examples of in vitro inducers for P450-mediated metabolism (9/26/2016)
表1-3. p450介导的体外代谢诱导剂的例子(9/26/2016)

Enzyme 酶Inducer* 诱导物 *CYP1A2Omeprazole, Lansoprazole 奥美拉唑,兰索拉唑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介导的代谢(用于指数临床 DDI 研究)的临床指数底物示例(9/26/2016)

Sensitive index substrates unless otherwise noted 敏感的索引基板,除非另有说明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- 华法林(c)CYP2C19 2c19lansoprazole (c,d), omeprazole 兰索拉唑(c,d)奥美拉唑CYP2D6desipramine, dextromethorphan, nebivolol 地昔帕明,右美沙芬,奈比沃洛尔CYP3A 细胞色素 p3amidazolam, triazolam 咪达唑仑,三唑仑


* 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: 指数基质可预见地表现出暴露增加由于抑制或诱导给定的代谢途径,并通常用于前瞻性临床 DDI 研究。见第四节 a. 2。有关详情,请参阅主要临床 DDI 指引文件。敏感指数底物是指数药物,在临床 DDI 研究中表明,在给定代谢途径的强指数抑制剂的作用下,AUC 增加≥5倍。中度敏感的底物是在临床 DDI 研究中显示 AUC ≥2到 < 5倍增加的药物,并且使用给定代谢途径的强指数抑制剂。
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.
此表准备提供临床敏感或中等敏感指数基板的例子,并不打算是一个详尽的清单。本表中列出的指数基质是根据其敏感性、特异性、安全性和足够数量的已报道的不同体内抑制剂(CYP3A ≥3或 CYP1A2、2C8、2C9、2c19和2d6≥2)的临床 DDI 研究选择的。DDI 数据是基于对华盛顿大学代谢与运输药物相互作用数据库的搜索而收集的[ 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)我们目前没有 cyp2b6的敏感指数底物。(b)亦为 oatp1b1底物。(c)中度感应强的基质。(d) s-兰索拉唑是 cyp2c19电镜检查的敏感底物。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1.
缩写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物-药物相互作用; EM: 广泛代谢物; OATP1B1: 有机阴离子转运多肽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介导代谢的临床指数抑制剂的例子(用于指数临床 DDI 研究)(9/26/2016)

Strong index inhibitors 强指数抑制剂Moderate index inhibitors 中等指数抑制剂CYP1A2fluvoxamine 氟伏沙明(a)-CYP2B6(b)--CYP2C8 2c8clopidogrel 氯吡格雷(c), gemfibrozil 吉非罗齐(d)-CYP2C9 2c9-fluconazole 氟康唑(e)CYP2C19 2c19fluvoxamine 氟伏沙明(a)-CYP2D6fluoxetine 氟西汀(f), paroxetine 帕罗西汀mirabegronCYP3A 细胞色素 p3aclarithromycin 克拉霉素(g), itraconazole ,伊曲康唑(g)erythromycin, fluconazole 红霉素,氟康唑(e), verapamil 维拉帕米(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: 指数抑制剂通过一个给定的途径可预测地抑制代谢,并且通常用于前瞻性临床 DDI 研究。见第四节 a. 2。详情请参阅主要指引文件。强抑制剂和中抑制剂是分别提高给定代谢途径敏感指数底物 AUC ≥5倍和≥2 < 5倍的药物。
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.
本表准备提供临床指数抑制剂的例子,并不打算是一个详尽的清单。本表所列的指数抑制剂是根据抑制的效力和选择性、安全性和足够数量的已报道的临床 DDI 研究,不同的体内底物[ CYP3A ≥3,CYP1A2,2C9,2c19和2d6≥2,或 CYP2C8(强抑制剂)≥1]筛选的。DDI 数据是基于对华盛顿大学代谢与运输药物相互作用数据库的搜索而收集的[ Hachad et al. (2010) ,Hum Genomics,5(1) : 61] ,参考文献列表可在此查阅。
(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的强抑制剂,cyp2d6和 CYP3A 的中度抑制剂。(b)我们目前没有 cyp2b6的指数抑制剂。
(c) cyp2c8的强抑制剂、 cyp2b6的弱抑制剂和 oatp1b1的抑制剂。葡萄糖苷类代谢物也是 cyp2c8和 oatp1b1的抑制剂。
(d) cyp2c8强抑制剂和 oatp1b1和 oat3强抑制剂。葡萄糖苷类代谢物也是 cyp2c8和 oatp1b1的抑制剂。
(e) cyp2c19强抑制剂和 CYP2C9、 CYP3A 中度抑制剂。
(f) cyp2c19和 cyp2d6的强抑制剂(g) P-gp 的抑制剂(定义为地高辛的 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.
简写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物相互作用; OATP1B1: 有机阴离子转运多肽1b1; OAT3: 有机阴离子转运蛋白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介导代谢的临床指数诱导剂实例(用于指数临床 DDI 研究)(9/26/2016)

Strong inducers 强大的诱导剂Moderate inducers 适度的诱导剂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 细胞色素 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: 指数诱导剂通过给定的途径诱导代谢,在前瞻性 DDI 临床研究中常用。见第四节 a. 2。详情请参阅主要指引文件。强指数诱导剂和中等指数诱导剂分别使给定代谢途径敏感指数底物的 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.
本表准备提供临床指数诱导物的例子,并不打算是一个详尽的清单。本表列出的指数诱导剂是根据诱导效力、安全性和已报道的使用不同体内基质(≥2个基质)进行的临床 DDI 研究数量选择的。DDI 数据是基于对华盛顿大学代谢与运输药物相互作用数据库的搜索而收集的[ 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 的强诱导剂和 CYP2B6、 CYP2C8、 cyp2c9的中等诱导剂;。(b) CYP3A 的强诱导剂和 CYP1A2、 cyp2c19的中度诱导剂。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.
缩写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物-药物相互作用。

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介导的代谢临床基质的例子(同时使用临床 DDI 研究和/或药物标记)(12/03/2019)

Sensitive substrates 敏感的基质Moderate sensitive substrates 适度敏感的基质CYP1A2alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine 阿洛司琼,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,雷莫司琼,茶碱CYP2B6bupropion 安非他酮(a)efavirenz 依法韦伦茨(a)CYP2C8 2c8repaglinide 瑞格列奈(b)montelukast, pioglitazone, rosiglitazone 孟鲁司特,吡格列酮,罗格列酮CYP2C9 2c9celecoxib 塞来昔布(c)glimepiride, phenytoin, tolbutamide, warfarin 格列美脲,苯妥英,甲苯磺丁脲,华法林CYP2C19 2c19S-mephenytoin, omeprazole S- 美苯妥英,奥美拉唑diazepam, lansoprazole 安定,兰索拉唑(d), rabeprazole, voriconazole ,雷贝拉唑,伏立康唑CYP2D6atomoxetine, desipramine, dextromethorphan , eliglustat 阿托莫西汀,地昔帕明,右美沙芬,埃利格鲁司特(e), nebivolol, nortriptyline, perphenazine, tolterodine, R-venlafaxine )、奈比洛尔、去甲替林、奋乃静、托特罗定、右文拉法辛encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, trimipramine, S-venlafaxine 恩卡尼,丙咪嗪,美托洛尔,普罗帕酮,心得安,曲马多,曲米帕明,s- 文拉法辛CYP3A 细胞色素 p3aalfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir ****,阿凡那非,丁螺环酮,科尼帕坦,达非那新,达鲁那韦(f), ebastine, everolimus, ibrutinib, lomitapide, lovastatin 依巴斯汀,依莫莫司,依布鲁替尼,洛米他滨,洛伐他汀(g), midazolam, naloxegol, nisoldipine, saquinavir ,咪达唑仑,纳络酮,尼索地平,沙奎那韦尔(f), simvastatin 辛伐他汀(g), sirolimus, tacrolimus, tipranavir 西罗莫司,他克莫司,替普那韦(f), triazolam, vardenafil 三唑仑,伐地那非alprazolam, aprepitant, atorvastatin 阿普唑仑,阿普匹坦,阿托伐他汀(c), colchicine, eliglustat 秋水仙碱,eliglustat(e), pimozide, rilpivirine, rivaroxaban, tadalafil 皮莫齐德,利匹韦林,利伐洛沙班,他达拉非budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir 布地奈德,达沙替尼,卓尼达龙,依替普坦,依普列酮,非洛地平,依地那韦(f), lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 卢拉西酮,马拉维洛克,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: 敏感底物是指在临床 DDI 研究中显示 AUC ≥5倍增长的药物,并且使用给定代谢途径的强指数抑制剂。中度敏感的底物是在临床 DDI 研究中显示 AUC ≥2到 < 5倍的药物,并且使用给定代谢途径的强指数抑制剂。在虚线上方显示了与强指数抑制剂共同给药使 AUC 增加≥10倍的 CYP3A 敏感底物。其他消除途径也可能有助于消除上表所列底物,在评估药物相互作用潜力时应予以考虑。
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].
本表准备提供临床基础的例子,并不打算是一个详尽的清单。DDI 数据是基于华盛顿大学代谢与运输药物相互作用数据库的搜索而收集的[ 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)根据体内诱导研究列出,观察到的效应可能部分归因于其他途径的诱导。(b) oatp1b1底物。
(c)根据药物遗传学研究列出。
(d) s-兰索拉唑是 cyp2c19电镜检查的敏感底物。
(e) cyp2d6的敏感底物和 CYP3A 的中度敏感底物。
(f)通常与强效 CYP3A 抑制剂利托那韦联合使用。
(g)酸形式为 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.
缩写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物-药物相互作用; EM: 广泛代谢物; OATP1B1: 有机阴离子转运多肽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: 临床抑制剂的例子 p450介导的代谢(同时使用临床 DDI 研究和/或药物标记)(03/06/2020)

Strong inhibitors 强效抑制剂Moderate inhibitors 中度抑制剂Weak inhibitors 弱抑制剂CYP1A2ciprofloxacin, enoxacin, fluvoxamine 环丙沙星,依诺沙星,氟伏沙明(a)methoxsalen, mexiletine ,oral contraceptives 甲氧沙林,美西律,口服避孕药acyclovir, allopurinol, cimetidine, peginterferon alpha-2a, piperine, zileuton 阿昔洛韦,别嘌呤醇,西咪替丁,聚乙二醇干扰素 α-2a 胡椒碱,齐留通CYP2B6--clopidogrel 氯吡格雷(b), tenofovir, ticlopidine ,替诺福韦,噻氯匹定(c), voriconazole 伏立康唑(voriconazole)(d)CYP2C8 2c8gemfibrozil 吉非罗齐(e)clopidogrel 氯吡格雷(b), deferasirox, teriflunomide 地拉罗司,特利氟米特trimethoprim 甲氧苄啶CYP2C9 2c9-amiodarone, fluconazole 胺碘酮,氟康唑(f), miconazole, piperine ,咪康唑,胡椒碱diosmin, disulfiram, fluvastatin, fluvoxamine 地奥司明,双硫仑,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 联苯胺酸盐omeprazole, voriconazole 奥美拉唑,伏立康唑CYP2D6bupropion, fluoxetine 安非他酮,氟西汀(g), paroxetine, quinidine 帕罗西汀,奎尼丁(h), terbinafine 特比奈芬abiraterone, cinacalcet, duloxetine, lorcaserin, mirabegron 阿比特龙,西那卡塞,度洛西汀,氯卡色林,米拉贝根amiodarone, celecoxib, cimetidine, clobazam, cobicistat, escitalopram, fluvoxamine 胺碘酮,塞来昔布,西咪替丁,氯巴占,复方西酞普兰,氟伏沙明(a), labetalol, ritonavir 拉贝洛尔,利托那韦(h,i,j) (h,i,j), sertraline, vemurafenib 舍曲林,维莫拉非尼CYP3A4boceprevir, cobicistat Boceprevir copicstat(h), danoprevir and ritonavir 丹诺普瑞和利托那韦(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)、洛匹那韦(lopinavir)、利托那韦(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 目的研究利托那韦(ritonavir,h,j)、沙奎那韦(saquinavir)和利托那韦(ritonavir)的抗菌作用(h,j) (h,j), telaprevir ,telapreir(h), tipranavir and ritonavir 提普那韦和利托那韦(h,j) (h,j), telithromycin, troleandomycin, voriconazole )、特利红霉素、曲列安霉素、伏立康唑aprepitant, ciprofloxacin, conivaptan 安眠药,环丙沙星,尼伐普坦(l), crizotinib, cyclosporine, diltiazem 目的: 研究环孢霉素(cyclosporine)、克唑替尼(crizotinib)、地尔硫卓(diltiazem)、环孢霉素(cyclosporine)、地尔硫(m), dronedarone 我是 dronedarone(h), erythromycin, fluconazole ,红霉素,氟康唑(f), fluvoxamine 氟伏沙明(a), imatinib, tofisopam, verapamil 伊马替尼,托非索泮,维拉帕米(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 洛米他滨,雷尼替丁,雷诺嗪(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,奈非那韦(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: 强、中、弱抑制剂分别是增加给定代谢途径敏感指数底物 AUC ≥5倍,≥2 ~ < 5倍,≥1.25 ~ < 2倍的药物。在虚线上方显示强烈的 CYP3A 抑制剂,使敏感指数底物的 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].
本表准备提供临床抑制剂的例子,并不打算是一个详尽的清单。DDI 数据是在华盛顿大学代谢与运输药物相互作用数据库的搜索基础上收集的[ 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的强抑制剂。CYP3A 的中度抑制剂和 cyp2d6的弱抑制剂。(b) cyp2c8的中度抑制剂和 cyp2b6的弱抑制剂。
(c) cyp2c19强抑制剂和 cyp2b6弱抑制剂。
(d) cyp2c19和 CYP3A 的强抑制剂和 cyp2b6的弱抑制剂。
(e) cyp2c8的强抑制剂和 oatp1b1和 oat3的强抑制剂。
(f) cyp2c19的强抑制剂和 CYP2C9、 CYP3A 的中度抑制剂;。
P-gp 抑制剂(定义为地高辛 AUC 增加到≥1.25倍)。
(i) CYP3A 的强抑制剂和 cyp2d6的弱抑制剂。
(j)利托那韦在临床上通常与其他抗 hiv 或抗 hcv 药物联合使用。在推断单独使用利托那韦对联合方案对 CYP3A 活性的影响时应该注意。
(k)葡萄柚汁的作用因品牌不同而有很大差异,并且与浓度、剂量和制剂有关。研究显示,当使用某种制剂(例如高剂量、双倍强度)时,它可被归类为「强效 CYP3A 抑制剂」 ; 当使用另一种制剂(例如低剂量、单倍强度)时,它可被归类为「中等程度的 CYP3A 抑制剂」。
(l)分类是根据静脉注射 conivaptan 进行的研究进行的。
(m)地尔硫卓使某些敏感 CYP3A 底物(如丁螺环酮)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.
简写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物相互作用; HIV: 人类免疫缺陷病毒; HCV: 丙型肝炎病毒; OATP1B1: 有机阴离子转运多肽1b1; OAT3: 有机阴离子转运蛋白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: 临床诱导剂 p450介导的代谢(同时使用临床 DDI 研究和/或药物标记)的例子(12/03/2019)

Strong inducers 强大的诱导剂Moderate inducers 适度的诱导剂Weak inducers 弱诱导剂CYP1A2phenytoin 苯妥英(a) rifampin(b), ritonavir 利福平(b)利托那韦(c,d) (c,d), smoking, teriflunomide ,吸烟,特利氟米特-CYP2B6carbamazepine 卡马西平(e)efavirenz 依法韦伦茨(e), rifampin 利福平(a)nevirapine, ritonavir 奈韦拉平,利托那韦(c, d) (c,d)CYP2C8 2c8-rifampin 利福平(a)-CYP2C9 2c9-enzalutamide 恩扎鲁他胺(g), rifampin 利福平(a)apalutamide, aprepitant, carbamazepine 阿帕鲁丁胺,阿帕匹坦,卡马西平(e), ritonavir 利托那韦(c, d) (c,d)CYP2C19 2c19rifampin 利福平(a)apalutamide, efavirenz 阿帕鲁他胺,依法韦伦兹(e,f) (e,f), enzalutamide Enzalutamide(g), phenytoin 苯妥英钠(b)ritonavir 利托那韦(c, d) (c,d)CYP3A 细胞色素 p3aapalutamide, carbamazepine 阿帕鲁胺,卡马西平(e), enzalutamide Enzalutamide(g), mitotane, phenytoin 米托坦,苯妥英(b), rifampin 利福平(a), St. John’s wort 圣约翰草(h)bosentan, efavirenz Bosentan,efavirenz(f), etravirine, phenobarbital, primidone 依曲韦林,苯***,普利米酮armodafinil, modafinil 阿莫达非尼,莫达非尼(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: 强诱导剂、中诱导剂和弱诱导剂分别使给定代谢途径敏感指数基质的 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].
本表准备提供临床指数诱导物的例子,并不打算是一个详尽的清单。DDI 数据是在华盛顿大学代谢与运输药物相互作用数据库的搜索基础上收集的[ 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 的强诱导剂和 CYP1A2、 cyp2c19的中度诱导剂。(b) CYP2C19、 CYP3A 的强诱导剂和 CYP1A2、 CYP2B6、 CYP2C8、 cyp2c9的中度诱导剂。
(c)中等剂量的 cyp1a2诱导剂,剂量为800毫克/天利托那韦(不与其他抗艾滋病毒药物合用)。低剂量利托那韦对 cyp1a2的影响尚不清楚。
(d) CYP2B6、 cyp2c9和 cyp2c19的弱诱导物。分类依据的是利托那韦本身(不与其他抗艾滋病毒药物一起)在100-200毫克/天剂量下进行的研究,尽管文献报道高剂量利托那韦的影响更大。
(e) CYP2B6、 CYP3A 的强诱导剂和 cyp2c9的弱诱导剂。
(f) CYP2B6、 cyp2c19和 CYP3A 的中度诱导物。
(g) CYP3A 的强诱导剂和 cyp2c9和 cyp2c19的中度诱导剂。
(h)圣约翰草的作用差别很大,并且取决于制剂。
(i)200mg/d 的莫达非尼对 CYP3A 的诱导作用较大,400mg/d 的莫达非尼对 CYP3A 的诱导作用较大;。
Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.
缩写: AUC: 浓度-时间曲线下面积; CYP: 细胞色素 P450; DDI: 药物-药物相互作用。

Table 4-1: Examples of in vitro substrates for transporters (9/26/2016)
表4-1: 转运蛋白体外基质的例子(9/26/2016)

Transporter 运输机Gene 基因Substrate 基质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 他林洛尔(c)Vinblastine 长春碱(c)BCRP 英国气候变化研究会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 染料木黄酮Prazosin 哌唑嗪(e)Sulfasalazine 柳氮磺吡啶OATP1B1, 1b1,OATP1B3 1b3SLCO1B1,SLCO1B3 1b3Cholecystokinin octapeptide(CCK-8) (g) 八肽胆囊收缩素(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 阿德福韦p-aminohippurate - 氨基马尿酸盐Cidofovir 西多福韦Tenofovir 替诺福韦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 二甲双胍(o)1-methyl-4-phenylpyridinium (MPP+) 美国 MPP+ 协会(o)Tetraethylammonium (TEA) 四乙基铵(TEA)(o)OCT2SLC22A2Metformin 二甲双胍(o)1-methyl-4-phenylpyridinium (MPP+) 美国 MPP+ 协会(o)Tetraethylammonium (TEA) 四乙基铵(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)也是燕麦片的基质。
(c)亦是 mrp2的底物。
(d)亦是 mrp3的底物。
(e)也是 P-gp 的基质。
(f)也是 NTCP 的基底。
(g) oatp1b3的选择性底物(vs. OATP1B1)。
(h)在抑制研究中估计 Ki 值较低。这种物质具有标记药物的特征。
(i) oatp1b1的选择性底物(vs. OATP1B3)。据报道,在抑制研究中的估计 Ki 值往往偏低。
(j)也是 BCRP 的底物。
(k)也是 oat3的底物。
(l) oatp1b3的选择性底物(vs. OATP1B1)。在研究系统中加入白蛋白可以减少非特异性吸收的影响。
(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.
本表准备提供各种转运蛋白的体外基质实例,并非详尽无遗的清单。

Table 4-2: Examples of in vitro inhibitors for transporters (9/26/2016)
表4-2: 转运蛋白体外抑制剂的例子(9/26/2016)

Transporter 运输机Gene 基因Inhibitor 抑制剂P-gpABCB1Cyclosporine 环孢霉素(a)Elacridar (GF120918)(b)Ketoconazole 酮康唑(c)Quinidine 奎尼丁(d)Reserpine 利血平(e)Ritonavir 利托那韦(f)Tacrolimus 他克莫司(f)Valspodar (PSC833)(e)Verapamil 维拉帕米(d)Zosuquidar (LY335979)BCRP 英国气候变化研究会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 环孢霉素(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 的抑制剂。
(b)也是 BCRP 的抑制剂。
(c)也是 NTCP 的抑制剂。
(d)也是 OCTs 的抑制剂。
(e)亦为 mrp2的抑制剂。
(f)亦是一种燕麦蛋白抑制剂。
(g)也是 P-gp 的抑制剂。
(h)在抑制研究之前用抑制剂进行预培养会导致 Ki 值下降。
(i)亦为 oat3的抑制剂。
This table is prepared to provide examples of in vitro inhibitors for various transporters and not intended to be an exhaustive list.
本表准备提供各种转运蛋白体外抑制剂的实例,并非详尽无遗的清单。

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: 转运蛋白临床基质(用于临床 DDI 研究和/或药物标签)的例子(12/03/2019)

Transporter 运输机Gene 基因Substrate 基质P-gpABCB1Dabigatran etexilate, digoxin, fexofenadine 达比加群依替西酯,地高辛,非索非那定(e)BCRP 英国气候变化研究会ABCG2 2rosuvastatin, sulfasalazine 瑞舒伐他汀,柳氮磺吡啶OATP1B1 1b1OATP1B3 1b3SLCO1B1,SLCO1B3 1b3asunaprevir, atorvastatin, bosentan, danoprevir, docetaxel 阿苏那普利,阿托伐他汀,波生坦,丹诺普利,多西他赛(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 燕麦3SLC22A6, 22a6,SLC22A8adefovir 阿德福韦(c), cefaclor, ceftizoxime, famotidine 头孢克洛,头孢唑肟,法莫替丁(d), furosemide, ganciclovir 速尿,更昔洛韦(c), methotrexate, oseltamivir carboxylate ,甲氨蝶呤,奥司他韦羧酸盐(d), penicillin G ,青霉素 g(d)MATE1, 1,MATE-2K, OCT2 MATE-2K,OCT2SLC47A1, SLC47A2, SLC22A2 47a1,SLC47A2,SLC22A2metformin 二甲双胍


Note:
Criteria for selecting clinical substrates are as follows:
注: 选择临床基质的标准如下:

  • 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)与维拉帕米或奎尼丁联合应用时 AUC 增高≥2,(2) P-gp 表达系统体外转运,但未见广泛代谢

  • 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)的药物遗传学改变和(2) BCRP 表达系统的体外转运

  • 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与利福平(单剂量)或环孢素 a 共同给药,或药物遗传学改变 SLCO1B1(521T > c)和(2) oatp1b1或 oatp1b3表达系统的体外转运

  • 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)丙磺舒联合给药后 AUC 倍增≥1.5,(2)尿液中未改变的药物排出尿液≥0.5,(3) oat1或 oat3表达系统体外转运

  • OCT2/MATE: Well-established substrate of cationic transport system (metformin). OCT2/MATE: 阳离子传递体系(二甲双胍)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].
本表提供了各种转运蛋白的临床基质的例子,并非详尽无遗的清单。DDI 数据是在华盛顿大学代谢与运输药物相互作用数据库的搜索基础上收集的[ 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)体外数据显示 oatp1b3比 oatp1b1有更高的贡献。体外和药物遗传学数据显示 oatp1b1的贡献率高于 OATP1B3。(c)体外数据显示 oat1比 oat3有更高的贡献。(d)体外数据显示 oat3的含量较 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.
缩写: AUC: 血浆浓度-时间曲线下面积。

Table 5-2: Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug labeling) (9/26/2016)
表5-2: 转运蛋白临床抑制剂的例子(用于临床 DDI 研究和药物标记)(9/26/2016)

Transporter 运输机Gene 基因Inhibitor 抑制剂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、卡维地洛、克拉霉素、德罗尼达罗、伊曲康唑、拉帕替尼、洛匹那韦、利托那韦、普罗帕酮、奎尼丁、雷诺嗪、利托那韦、替拉帕那韦、利托那韦、替拉帕那韦BCRP 英国气候变化研究会ABCG2 2curcumin, cyclosporine A, eltrombopag 姜黄素,环孢素 a,艾特罗布帕OATP1B1, OATP1B3 1b1,OATP1B3SLCO1B1, SLCO1B3 1b1,SLCO1B3atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin (single dose), simeprevir 阿扎那韦和利托那韦,克拉霉素,环孢霉素,红霉素,吉非罗齐,洛匹那韦和利托那韦,利福平(单剂量) ,西梅普韦韦OAT1, OAT3 1,OAT3SLC22A6, SLC22A8 22a6,SLC22A8p-aminohippuric acid (PAH) 对氨基马尿酸(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,杜鲁替拉韦,异恶康唑,雷诺嗪,甲氧苄啶,万德他尼


Note:
Criteria for selecting in vivo inhibitors are as follows:
注: 选择体内抑制剂的标准如下:

  • P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor. P-gp: (1)地高辛≥2与体外抑制剂联合应用时 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)与盐酸柳氮磺吡啶合用时,体外抗肿瘤作用明显增强(2)。环孢素 a 和 eltrombpag 也包括在内,虽然可用的 DDI 信息是与瑞舒伐他汀,其中 BCRP 和 oatp 的抑制可能有助于观察到的相互作用

  • 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至少一个临床底物在表2-3与联合给药和(2)体外抑制剂

  • 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至少有一个临床底物在表2-3与联合给药和(2)体外抑制剂。<.我 =””>

  • OCT2/MATE: (1) AUC fold-increase of metformin ≥ 1.5 with co-administration and (2) in vitro inhibitor. OCT2/MATE: (1)联合给药和体外抑制剂使二甲双胍≥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].
本表准备提供各种转运蛋白的临床抑制剂的例子,并非详尽无遗的清单。DDI 数据是在华盛顿大学代谢与运输药物相互作用数据库的搜索基础上收集的[ 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)大多数 P-gp 抑制剂也抑制 CYP3A。(b)体内数据表明 oat1具有特异性抑制作用。
Abbreviations:
AUC: area under the plasma concentration-time curve.
缩写: AUC: 血浆浓度-时间曲线下面积。
References
参考资料
Ministry of Health, Labour and Welfare (MHLW), Japan (2014). Drug interaction guideline for drug development and labeling recommendations (Draft, in Japanese)
日本厚生劳动省(厚生劳动省)(2014年)。药物相互作用指南药物开发和标签建议(草案,日文)
European Medicines Agency (2013). Guideline on the Investigation of Drug Interactions.
欧洲药物管理局药物相互作用研究指南(2013)。


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