CN1479628A - Cyp2d6抑制剂在联合治疗中的用途 - Google Patents
Cyp2d6抑制剂在联合治疗中的用途 Download PDFInfo
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- CN1479628A CN1479628A CNA008056188A CN00805618A CN1479628A CN 1479628 A CN1479628 A CN 1479628A CN A008056188 A CNA008056188 A CN A008056188A CN 00805618 A CN00805618 A CN 00805618A CN 1479628 A CN1479628 A CN 1479628A
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- officinal salt
- medicine
- cyp2d6
- cpy2d6
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Abstract
本发明涉及CPY2D6抑制剂与具有CPY2D6催化代谢的药物联合给药的用途，其中该药物和CPY2D6抑制剂不是同一种化合物；以及用于所述用途的药物组合物。
Description
发明背景
本发明涉及CYP2D6抑制剂用于与具有CYP2D6催化代谢的药物联合从而改善该药物的药代动力学分布图的用途。
药物在人体内的清除可以有几种机制，诸如代谢、尿液排泄、胆汁排泄等。尽管存在许多种清除机制，但在人体，药物的大部分还是通过肝脏代谢的。肝脏代谢可包括氧化(例如，羟基化、杂原子脱烷基化)和共轭(例如葡糖醛酸化(glucuronidation)、乙酰化)反应。另外，尽管有许多可能的代谢反应类型，但大多数药物还是经氧化途径代谢的。因此，绝大多数药物的清除的主要途径是肝脏的氧化代谢。
在药物的氧化代谢所涉及的酶中，细胞色素P-450(CYP)酶总科起到重要作用。CYP包括种类超过200种的酶，这些酶能够对很大范围的异生化合的底物结构催化多种氧化反应(经假设的通用反应机制)。在人体中，大多数药物的CYP催化的代谢由五种异构体之一进行，这五种异构体是：CYP1A2、CYP2C19、CYP2C9、CYP2D6和CYP3A4之一进行，后面三种是这些酶中最重要的。
在所有已知的CYP异构体中，对其作用底物了解最多的是CYP2D6。该异构体几乎独有地包含于亲脂性胺药物的氧化代谢中。公知的CYP2D6底物包括神经松弛剂、1C型抗心律失常药、β-阻滞剂、抗抑郁剂(三环抗抑郁剂、选择性5-羟色胺重摄取抑制剂和单胺氧化酶抑制剂)，以及其它诸如可待因和右甲吗喃药物。这些以胺作为底物的明显的特异性被推测是由于在底物的结合位点存在酸性氨基酸残基。这种残基在接近CYP的亚铁血红素活性铁中心定位用于氧化的位点时可与胺底物形成离子相互作用。CYP2D6和胺代谢的结构活性关系已经引起建立了一个关于这个酶的推测模式，其中认为CYP2D6底物的氧化位置是距离碱性胺的氮原子5到7的地方。还有一些另外的关于空间结构必要条件的假说。
其在人体的主要清除机制是CYP2D6介导的氧化生物转化的很多化合物，一般表现一种或多种对于人体药代动力学有害的特性。这些特性是：(1)就暴露(expsure)而言具有和缺乏CYP2D6基因考贝的个体之间极大的不均等，(“强代谢者和弱代谢者”)；(2)就暴露而言强代谢者之间的个体间差异较高；(3)比例上的用药剂量-暴露关系的倾向。(4)频繁的药物-药物相互作用；和(5)由于广泛的肝脏清除首过效应导致较短的半衰期和较差的口服生物利用率。
不是所有的CYP2D6底物都具有这些特性，大多数CYP2D6底物只有一到多种这些效应。
在八十年代中期，曾进行过关于一小部分人群暴露于药物中的差异的观察。在一些情况下，在少数个体暴露于高剂量药物的情况下观察到一些相关的负反应。这些观察导致发现CYP2D6遗传多态性。在5-10％的高加索人群(被称为弱代谢者或PM`s)中缺乏CYP2D6基因。这些个体可通过经由限制片断长度多态现象分析检查基因型，或通过在服用后一种化合物后测定尿右羟吗喃/右甲吗喃比率确定表型而从其它人群中区别出来。当做出暴露于原型CYP2D6清除的化合物的人群柱状图时，可以观察到双峰分布。例如，一种公知的CYP2D6清除的化合物普罗帕酮的最后阶段的平均半衰期，在弱代谢者中是5.5小时，在弱代谢者中是17.2小时。在口服CYP2D6清除的化合物时，由于在首过排除中很大的不均等EM-PM差异典型地加剧。在口服后普罗帕酮暴露，在PM`s中是EM`s的4.2倍。因此，由于在PM`s中观察到的系统暴露的升高，CYP2D6清除的化合物可遇到负作用的发生率增加的问题。
不考虑遗传多态性，在那些被认为是强代谢者的个体中，暴露于CYP2D6清除的化合物存在个体间高度差异性。关于这种差异的原因目前尚不知道，这似乎不是由于CYP2D6基因考贝数增加的缘故(尽管在瑞典的一篇文献中报道过一种这样的基因型)，似乎也不是由于环境因素，因为这种CYP异构体从来没有显示过可以被诱导。这种差异现象的例子可通过施用抗抑郁药丙咪嗪和它的代谢物去甲丙咪嗪显示，它显示在口服后20倍范围的稳定状态的血浆浓度。对于有较广的治疗指数的化合物，这种差异性可能不成问题。然而，如果CYP2D6清除的化合物的治疗指数接近10，就可能观察到负作用的发生率增加。
代谢清除是一个潜在的可饱和的过程。内源性清除(CT`int，没有由器官的血流或血浆蛋白结合造成的限制的器官清除化合物的能力)是Michaelis-Menten参数的函数：
这里，Vmax和KM都是固定的常数，[S]代表在清除器官内的药物浓度。对于大多数药物来说，在体内一般达到的药物浓度远远低于KM，因此，上面的表达式的分母简化成KM的常数值。然而，对于许多CYP2D6催化的反应，KM值一般很低。这被推测是由于在CYP2D6的底物结合位点的阳离子胺底物与氨基酸阴离子之间形成强(相对于其它CYP酶来说)离子键的缘故。因此对于CYP2D6清除的化合物，药物浓度可接近或超过KM值，导致内源性清除值随药物浓度的增加而降低。由于药物浓度与剂量相关，观察到清除随着药物剂量的增加而降低。伴随着因剂量增加而导致的清除降低，观察到随之剂量增加血药浓度以超比例的方式增加。这种关系在关于CYP2D6清除的化合物普罗帕酮和氟苯哌苯醚的科学文献中进行了描述。有趣的是，这种现象在弱代谢者的情况下观察不到，因为CYP2D6同工型不存在于这些个体中。
参数KM是酶反应速率常数的复合函数，对于CYP，有一个强的底物结合速率常数成分。潜在存在的是一种药物代谢的竞争性抑制可以经催化竞争性底物结合第二种药物而发生。由于CYP酶的KM与结合常数密切相关，在很多情况下它们接近Ki值。对于CYP2D6，典型底物的低的KM值也可导致这些相同底物用作竞争性抑制剂时的低的Ki值。低的Ki值反映有很大的导致药物-药物相互作用的潜力，因为低浓度和剂量的药物已足以显示出抑制。因此药物-药物相互作用潜力与CYP2D6底物比其它CYP底物更相关，因为前者有更大的结合亲和力。因此，由于Ki值一般随同KM值，药物-药物相互作用的潜力通常与超比例的剂量-暴露关系的潜力并进。
如上面所提到的，清除与Vmax/KM项相关。对于具有相似的Vmax值的化合物来说，KM值越低，清除率越高。由于很多CYP2D6底物都具有很低的KM值，这些化合物，作为一组，在体内更有可能展现高的肝脏清除率。高的肝脏清除率导致较短的半衰期。它还可能导致较大的首过肝脏排除效应，这将引起低的口服生物利用率。这一点可通过下列化合物表现：(7S，9S)-2-(2-嘧啶基)-7-(琥珀酰胺甲基)-全氢-1H-吡啶并-[1，2-a]吡嗪(“苏尼帕卓(sunipetron)”)(KM约1μM，人体的半衰期约1小时)，(2S，3S)-2-苯基-3-(2-甲氧苯基)-甲胺基哌啶(KM约1μM，人体的半衰期约4.7小时)，(1S，2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇(KM约3-4μM，人体的半衰期约3-4小时)，和(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧苯基)-甲氨基-哌啶(KM约1μM，人体的半衰期约8小时)，所有这些都是CYP2D6底物。前面的两种化合物具有的KM值在1μM范围。这两种化合物的人体半衰期是1.1和4.7小时，这两种化合物的人体口服生物利用率分别是4.6和1.0％。在人体静脉内给药后，测定的前面两种化合物的清除值在血流限定值范围，提示肝的排除率超过90％。
这里有几种公知的抑制CYP2D6反应的化合物，是“纯”抑制或作为竞争性底物而起作用。与许多其它的CYP酶不同，有几种已知的有效的CYP2D6抑制剂。这里也认为在抑制剂的阳性胺基团和CYP2D6的阴性氨基酸残基之间存在的离子的相互作用，至少对CYP2D6抑制剂的作用有部分影响。有效的CYP2D6抑制剂的两个例子是奎尼丁和萝芙辛：
奎尼丁，Ki＝80nm 萝芙辛，Ki＝4.6nm
奎尼丁代表普遍使用的抗心律失常药，而萝芙辛则是一种很少有人知道的具有扩张血管活性的天然药品。由于奎尼丁是普遍使用的药物，关于这种药物和CYP2D6清除的化合物的药物相互作用已经进行了体内研究。奎尼丁具有通过对CYP2D6的抑制，转变强代谢者成为弱代谢者表型的作用。
另外，近来发现圣·约翰(St.John`s)麦芽汁提取物含有显示CYP抑制活性的组成物质，包括对CYP2D6的抑制。显示CYP抑制活性的St.John`s提取物组成物质的例子是贯叶金丝桃素13，118-双芹菜[苷]配基、金丝桃素、栎皮酮。其它不确定的成分也显示具有CYP抑制活性。
对于CYP2D6清除的化合物，经常面临的一个问题是在强代谢者和弱代谢者之间的暴露差异，以及强代谢者显示的高度差异。然而，常常忽略的一个问题是这些化合物在贫代谢者中一般具有非常令人满意的药代动力学特点。在缺乏CYP2D6酶的个体中，CYP2D6清除化合物：(1)一般具有长的t1/2值和高的口服生物利用率；和(2)不显示超比例的剂量-暴露关系。由于缺乏CYP2D6酶，在弱代谢者中的药物暴露的可变性不比由非CYP2D6清除的化合物显示的可变性大。尽管曾试图将弱代谢者状况与各种病理状态倾向联系起来，但确定的原因-效果关系还有待于建立。因此，由于弱代谢者代表正常和健康的人群，不能预测经服用特定的CYP2D6抑制剂使强代谢者转变成弱代谢者将导致任何与这种酶的抑制有关的不利效果。
本发明涉及使用CYP2D6抑制剂和CYP2D6清除的化合物的共配方或联合使用。因此，与避免药物-药物相互作用不同，本发明包括特意发展这种相互作用，以改善利于治疗的药代动力学，但药代动力学无效的化合物除外。这种方法与利用缓释制剂以增强药物的药代动力学的方法相似。然而，与经输入率限制以调节药物的消除的方法不同，该方法寻求通过直接调制消除率来达到同样的效果。另外，除了延长半衰期以外，CYP2D6抑制剂由于抑制了肝的首过排除而增强了口服暴露量。
本发明概述
本发明涉及一种其在人体的主要清除机制是CYP2D6介导的氧化生物转化(在本文中也被称为“治疗用药物”)的药物或它的可药用盐，与CYP2D6抑制剂或它的可药用盐结合，用于需要这种药物的预期的药学活性的人体的给药方法，其中治疗用药物和CYP2D6抑制剂不是同一种化合物。上面的方法在下文中被称为“联合方法”。
本发明还涉及这样的联合方法，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的选择性5-羟色胺重摄取抑制剂(例如舍曲林或氟西汀)。
本发明还涉及这样的联合方法，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的NMDA(N-甲基-D-天冬氨酸)受体拮抗剂。
本发明还涉及这样的联合方法，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的神经激肽-1(NK-1)受体拮抗剂。
本发明还涉及这样的联合方法，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的三环抗抑郁药(例如去甲丙咪嗪、丙咪嗪或氯米帕明)。
在涉及该联合方法的本发明的优选实施方案中，其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物，是(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧基苯基)甲氨基-哌啶或它的可药用盐。
在涉及该联合方法的本发明的优选实施方案中，其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是苏尼帕卓或它的可药用盐。
苏尼帕卓具有如下结构
其中Y是具有下式结构的基团
在涉及该联合方法的本发明的另一个优选实施方案中，其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是(1S，2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇或它的可药用盐。
其在人体的主要清除机制是CYP2D6介导的氧化生物转化的其它药物的例子如下：美喹地嗪(J.Pharmacol.Exp.Ther.，284，437-442(1998))；坦洛新(Xenobiotica，28，902-22(1998))；奥昔布宁(Pharmacogen.，8，449-51(1998))；利托纳维(ritonavir)(Clin.PK，35，275-291(1998))；伊潘立酮(J.Pharmacol.Exp.Ther.，286，1285-93(1998))；伊波加因(Drug Metab.Dispos.，26，764-8(1998))；迪拉维丁(delavirdine)(Drug Metab.Dispos.，26，631-9(1998))；托持瑞丁(tolteridine)(Clin.Pharmcol.，Ther.，63，529-39(1998))；异丙嗪(Rinshoyakon，29，231-38(1998))；匹莫齐特，J.Pharmacol.Exp.Ther.，285，428-37(1998))；伊匹斯汀(Res.Comm.Md.Path.Pharmacol.，98，273-92(1997))；曲马朵(Eur.J.Clin.Pharm.53，235-39(1997))；普鲁卡因胺(Pharmacogenetics，7，381-90(1997))；去氧麻黄碱(Drug Metab.Dispos.，25，1059-64(1997))；他莫昔芬(Cancer Res.，57，3402-06(1997))；尼麦角林(Br.J.Pharm.，42，707-11(1997))；和氟西汀(Clin.Pharmcol.Ther.60，512-21(1996)).所有前述参考文献作为整体一并在这里用作参考。
其在人体的主要清除机制是沿其各自的CYP2D6介导的氧化生物转化的路径(例如，脱甲基化、羟基化等)的CYP2D6介导的氧化生物转化的其它药物的例子，都可以从M.F.Fromm等编著的Advanced Drug Delivery Reviews，27，171-199(1997)查阅到，如下；烯丙心安、阿米夫胺、阿米替林、茚满丙二胺、溴法罗明、布图拉罗(buturalol)、肉桂苯哌嗪、氯丙咪嗪、可待因、异奎呱、去甲丙咪嗪、去甲西酞普兰、右芬氟拉明、右甲吗喃、二氢可待因、多拉斯琼、哌茴苯胺、乙基吗啡、哌氟酰胺、氟苯桂嗪、三氟戊肟胺、胍生、氟哌啶醇、二氢可待因酮、吲哌胺、丙咪嗪、麦普替林、甲氧苯丙胺、喘咳宁、甲撑二氧去氧麻黄碱、甲氧乙心安、慢心律、甲苯吡罩、苯哒吗林、普鲁可待因(procodeine)、去甲替林、N-丙基阿义马林(N-propylajmaline)、奥丹亚龙、羟氢可待因、氟苯哌苯米、环己哌啶、奋乃静、苯乙双胍、异丙嗪、苯乙酰苯心安、萘心安、利螺环酮、鹰爪豆碱、甲硫哒嗪、噻吗心安、托模西汀、托比色创、文拉法星和珠氯噻醇。
在涉及该联合方法的本发明的其它优选实施方案中被用于这种方法中的CYP2D6抑制剂或它的可药用盐，是奎尼丁或萝芙辛，或这些化合物之一的可药用盐。
在涉及该联合方法的本发明的其它优选实施方案中被用于这种方法中的CYP2D6抑制剂或它的可药用盐是选自下列化合物和它们的可药用盐：舍曲林(J.Clin.Psychopham.，18，55-61(1998))；文拉法星(Br.J.Pharm.43，619-26(1997))；右美托咪定(DMD，25，651-55(1997))；曲喷尼胺(tripennelamine)，普利马塞嗪(premethazine)，羟嗪(DrugMetab.Dispos.26，531-39，(1998))；卤福林坦(halofrintane)和氯喹(Br.J.Clin.Pharm.45，315-(1998))；和吗氯贝胺(Psychopharm.，135，22-26(1998)).
在涉及该联合方法的本发明的其它优选实施方案中被用于这种方法中的CYP2D6抑制剂或它的可药用盐，是St.John`s麦芽汁或一种提取物，或它的组成物。
本发明还涉及一种药物组合物，包括：
(a)治疗有效量的药物，其在人体的主要清除机制是CYP2D6介导的氧化生物转化(在该全文中被称为“治疗药物”)，或它的可药用盐。
(b)一定量的CYP2D6抑制剂，或它的可药用盐，它对于治疗(a)中提到的治疗药物将治疗的紊乱或病症有效。
(c)可药用载体。
其中所说药物和CYP2D6抑制剂不是相同的化合物。
上面的药物组合物在下面被称为“联合药物组合物”
本发明的优选实施方案涉及联合药物组合物，其中包含在所述药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物，或它的可药用盐是(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧基苯基)甲氨基哌啶或它的可药用盐。
本发明的其它优选实施方案涉及这样的联合药物组合物，其中包含在所述的药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物或它的可药用盐是(1S，2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇或它的可药用盐。
本发明的其它优选实施方案涉及这样的联合药物组合物，其中包含在所述的药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物或它的可药用盐是苏尼帕卓或它的可药用盐。
本发明的其它优选实施方案涉及这样的联合药物组合物，其中包含在所述的药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物，或它的可药用盐是选自下列化合物和它的可药用盐：甲奎酚嗪(J.Pharmacol.Exp.Ther.，284，437-442(1998))；坦洛新(Xenobiotica，28，902-22(1998))；奥昔布宁(Pharmacogen.，8，449-51(1998))；ritonavir(Clin.PK，35，275-291(1998))；伊潘立酮(J.Pharmacol.Exp.Ther.，286，1285-93(1998))；伊波加因(Drug Metab.Dispos.，26，764-8(1998))；delavirdine(Drug Metab.Dispos.，26，631-9(1998))；托特罗定(Clin.Pharmcol.，Ther.，63，529-39(1998))；异丙嗪(Rinshoyakon，29，231-38(1998))；匹莫齐特J.Pharmacol.Exp.Ther.，285，428-37(1998))；伊匹斯汀(Res.Comm.Md.Path.Pharmacol.，98，273-92(1997))；曲马朵(Eur.J.Clin.Phar.53，235-39(1997))；普鲁卡因胺(Pharmacogenetics，7，381-90(1997))；去氧麻黄碱(Drug Metab.Dispos.，25，1059-64(1997))；他莫昔芬(Cancer Res.，57，3402-06(1997))；尼麦角林(Br.J.Pharm.，42，707-11(1997))；和氟西汀(Clin.Pharmcol.Ther.60，512-21(1996)).所有前述参考文献一并在这里用作参考其中各项。
本发明的其它优选实施方案涉及这样的联合药物组合物，其中包含在所述药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物，或它的可药用盐是选自下列化合物和它的可药用盐：连同其各自的CYP2D6介导的氧化生物转化的路径(例如，O-脱甲基化、羟基化等)它们都可以从M.F.Fromm等编著的Advanced Drug Delivery Reviews，27，171-199(1997)查阅到，如下；烯丙心安、阿米夫胺、阿米替林、茚满丙二胺、溴法罗明、布图拉罗、肉桂苯哌嗪、氯丙咪嗪、可待因、异奎呱、去甲丙咪嗪、去甲西酞普兰、右芬氟拉明、右甲吗喃、二氢可待因、多拉斯琼、哌茴苯胺、乙基吗啡、哌氟酰胺、氟苯桂嗪、三氟戊肟胺、胍生、氟哌啶醇、二氢可待因酮、吲哌胺、丙咪嗪、麦普替林、甲氧苯丙胺、喘咳宁、甲撑二氧去氧麻磺碱、甲氧乙心安、慢心律、甲苯吡、苯哒吗林、普鲁司特因、去甲替林、N-丙基阿义马林、奥丹亚龙、羟氢可待因、氟苯哌苯米、环己哌啶、奋乃静、苯乙双胍、异丙嗪、苯乙酰苯心安、萘心安、利螺环酮、鹰爪豆碱、甲硫哒嗪、噻吗心安、托莫西汀、托比色创、文拉法星和珠氯噻醇。
本发明的其它优选实施方案涉及这样的联合药物组合物，其中包含在所述药物组合物中的其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物，或它的可药用盐是选自下列化合物和它的可药用盐：舍曲林(J.Clin.Psychopham.，18，55-61(1998))；文拉法星(Br.J.Pharm.43，619-26(1997))；右美托咪定(DMD，25，651-55(1997))；tripennelamine，premethazine，羟嗪(Drug Metab.Dispos.26，531-39，(1998))；halofrintane和氯喹(Br.J.Clin.Pharm.45，315-(1998))；和吗氯贝胺(Psychopharm.，135，22-26(1998)).
涉及该联合方法的本发明的其它优选实施方案，其中被用于这种方法中的CYP2D6抑制剂或它的可药用盐，是St.John`s麦芽汁或一种它的提取物，或组成物。
本发明还涉及这样的联合药物组合物，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的选择性5-羟色胺重摄取抑制剂(例如舍曲林或氟西汀)。
本发明还涉及这样的联合药物组合物，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的NMDA(N-甲基-D-天冬氨酸)受体拮抗剂。
本发明还涉及这样的联合药物组合物，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的神经激肽-1(NK-1)受体拮抗剂。
本发明还涉及这样的联合药物组合物，其中其在人体的主要清除机制是CYP2D6介导的氧化生物转化的药物是包含伯、仲或叔烷基胺基团的三环抗抑郁药(例如去甲丙咪嗪、丙咪嗪或氯米帕明)。
这里所用的术语“治疗”，涉及逆转、减缓、抑制病程，或避免紊乱，或这一术语应用的，一种或多种这种状况或紊乱症状。这里所用的术语“治疗”涉及治疗的效果，如上面所定义的“治疗”一样。
这里所用的术语“CYP2D6介导的氧化转化”是指CYP2D6催化的氧化反应(如苄型、芳香族或脂肪族羟基化，O-脱烷基化、N-脱烷基化、侧链、磺化氧化作用)，通过这些反应进行CYP2D6底物药物的代谢。发明的详细说明
本发明涉及两种联合治疗方法，其中之一的治疗用药物或它的可药用盐，和CYP2D6抑制剂或它的可药用盐作为相同的药物组合物的一部分共同服用，另一种方法中，这两种活性剂作为设计获得联合治疗效果的适当剂量方案的一部分分开服用。
合适的剂量方案、每种药物的服用剂量、每个活性剂的剂量间的特定间隔将根据要治疗的病人、病源和病情严重程度而定。一般来讲，在执行本发明的方法时，治疗药物服用的剂量范围是，从大大低于已知的单独使用治疗用药物(即作为单一活性剂)的有效和治疗可接受的量一个数量级，到已知的单独使用治疗用药物时有效并治疗可接受的量。例如，对于一个平均体重(约70公斤)的成年人来说，(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧基苯基)甲氨基哌啶的用量范围是5到1500毫克/天，单剂量服用或分几次服用，优选0.07到21毫克/公斤。对于一个平均体重的成年人来说，(1S，2S)-1-(4-羟基苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇或它的可药用盐的用量范围是0.02毫克到250毫克/天，单剂量服用或分几次服用，优选0.15到250毫克/天。对于一个平均体重的成年人来说，苏尼帕卓的用量范围是2到200毫克/天单剂量服用或分几次服用。尽管如此，但根据接受治疗的病人的身体状况和他或她对所述药物的个人反应，以及所选药物配方的类型和服用该种药物的周期和间隔时间都可以有变化。在一些情况下，低于前述范围低限的剂量水平可能早已足够，而在另一些情况下，在不产生有害的副作用的情况下，也可以服用较大剂量，只要这种大剂量首先分成几份小剂量，在一天内分次服用。
治疗用药物，例如；(7S，9S)-2-(2-嘧啶基)-7-(琥珀酰胺甲基)-全氢-1H-吡啶并[1，2-a]吡嗪基)(“苏尼帕卓”)，(2S，3S)-2-苯基-3-(2-甲氧苯基)-甲氨基哌啶，(1S，2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇，(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧苯基)甲氨基哌啶，和CYP2D6抑制剂及其可药用盐(治疗用药物和CYP2D6抑制剂，以及他们的可药用盐下面也被单独或总称为“活性剂”)，可以分开或一起服用，每个或两种一起与可药用载体或稀释剂结合于单份或多剂量中。尤其是，这种药物可以以各种不同的制剂形式服用，即它们可以与各种各样形式的可药用惰性载体结合于下列形式中：如片剂、胶囊、锭剂、含片、硬糖果、粉剂、喷雾剂、霜剂、药膏、栓剂、凝胶、胶冻、糊剂、洗液、膏剂、水性悬浮液、注射用溶液、酏剂、糖浆等。这些载体包括固体稀释剂或填充剂、灭菌含水介质和各种无毒性有机溶剂等。另外，口服的药物组合物可以略加甜味和/或香味。一般来讲，存在于这种药剂形式的每种或两种前述活性剂的浓度水平按重量计在约5.0％到70％范围。
对于口服药，包含各种赋形剂(如微晶纤维素、柠檬酸钠、碳酸钙、磷酸钙和氨基乙酸)的片剂，可与各种崩解剂，如淀粉(优选玉米、马铃薯或木薯淀粉)、藻酸和某种复合硅酸盐，以及如聚乙烯吡咯烷酮、蔗糖、凝胶和阿拉伯树胶这类颗粒粘合剂一起使用。另外，诸如硬脂酸镁、十二烷基硫酸钠和滑石这样的润滑剂在制备片剂时非常有用。也可以使用相似类型的固体组合物作为明胶胶囊的填充物；与此有关的优选材料还包括乳糖或奶糖以及高分子量聚乙二醇。当需要水性悬浮液和/或酏剂用于口服时，活性成分可以结合各种甜或香料、色素或染料，并且，如果需要，还有乳化和悬浮剂，与稀释剂诸如水、乙醇、丙二醇、丙三醇以及它的各种类似组合。
对于肠胃外服用，可以使用用于本发明的方法的活性剂，或它们的可药用盐，任一种或者两者都有的在芝麻油或花生油或水性丙二醇中的溶液。如果需要，含水溶液应该是适当的缓冲液(优选pH大于8)并且液体稀释剂首先是等渗的。这些含水溶液适合用于静脉内注射目的。油性溶液适合关节内、肌肉和皮下注射目的。所有这些溶液的制剂在无菌条件下用本领域的技术人员所熟知的标准药学技术很容易获得。
另外，治疗皮肤的炎症时还可以局部施用用于本发明的方法的活性剂，或它们的可药用盐，任一种或者两者都有，这可以用霜剂、胶剂、凝胶、糊剂、贴剂、膏剂等，根据标准的药学方法制备。
在服用药物一段时间后，通过测定人血液、尿液或唾液中右甲吗喃和它的代谢物右吗喃的浓度可判断该个体是“弱代谢者”还是“强代谢者”。右甲吗喃/右吗喃的比率小于0.3定义为强代谢者者，该比率大于或等于0.3定义为弱代谢者者。这种表型的服用药物后适当的等待时间是：4到8小时作尿液测定，2到8小时作血浆测定，3到8小时作唾液测定。Schimidt等，Clin.Pharmacol.Ther.，38，618，1985中描述了这种方法。
下列方案可用于判断共同服用CPY2D6抑制剂和上面定义的治疗用药物对治疗用药物的药代动力学特征的影响。
方法：
1.预计为强代谢者的受试者(EM，具有功能性CPY2D6活性的个体)服用口服剂量的被测定为CPY2D6抑制剂的化合物。
2.同时，或服用CPY2D6抑制剂一段时间后，这些受试者服用一定剂量的、已知主要经CPY2D6介导的代谢清除的药物。
3.在服用CPY2D6清除的化合物的0时(剂量前)和预定时间点，从每个受试者采取几份血样。取样时间的例子是0.5，1，2，3，4，6，8，12，18，24，36，48和72小时。
4.用特定的生物分析方法(如带有紫外或质谱检测的HPLC)对血液(血浆或血清)进行CPY2D6清除的化合物检测。
5.CPY2D6清除的化合物的血浓度对时间作图，并从这些数据计算药代动力学。将要测量的药代动力学参数是在浓度对时间曲线下的面积(AUC)，最大浓度(Cmax)，最大浓度时间(Tmax)、清除率(CL)和半衰期(t1/2)。
6.试验的第二阶段包括给相同的受试者服用无CPY2D6抑制剂的CPY2D6清除的化合物。重复3-5步骤。(该研究的的两阶段的顺序不重要，只要有适当的彻底消除期即可)。
7.比较该研究的两个阶段的浓度对时间图和药代动力学参数，通过这个比较得出CPY2D6抑制剂的效果。
Claims (10)
1.一种给药方法，将其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物它的可药用盐，与CPY2D6抑制剂或它的可药用盐结合给药，用于需要该药物的预期的药学活性的个体，其中所述药物和所述CPY2D6抑制剂不是同一种化合物。
2.根据权利要求1的方法，其中其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物选自下组，该组包括：包含伯、仲或叔烷基胺基团的选择性5-羟色胺重摄取抑制剂；包含伯、仲或叔烷基胺基团的NMDA受体拮抗剂；包含伯、仲或叔烷基胺基团的神经激肽-1(NK-1)受体拮抗剂、包含伯、仲或叔烷基胺基团的三环抗抑郁药；和它们的可药用盐。
3.根据权利要求1的方法，其中其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物或它的可药用盐选自下组，该组包括：(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧苯基)甲氨基-哌啶、(1S，2S)-1-(4-羟基苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇、苏尼帕卓或其可药用盐。
4.根据权利要求1的方法，其中其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物或它的可药用盐选自下组，该组包括：甲奎酚嗪、坦洛新、奥昔布宁、利托纳维、伊潘立酮、伊波加因、迪拉维丁、托特罗定、异丙嗪、匹莫齐特、伊匹斯汀、曲马朵、普鲁卡因胺、去氧麻黄碱、他莫昔芬；尼麦角林、氟西汀、烯丙心安、阿米夫胺、阿米替林、茚满丙二胺、溴法罗明、布图拉罗、肉桂苯哌嗪、氯丙咪嗪、可待因、异奎呱、去甲丙咪嗪、去甲西酞普兰、右芬氟拉明、右甲吗喃、二氢可待因、多拉斯琼、哌茴苯胺、乙基吗啡、哌氟酰胺、氟苯桂嗪、三氟戊肟胺、胍生、氟哌啶醇、二氢可待因酮、吲哌胺、丙咪嗪、麦普替林、甲氧苯丙胺、喘咳宁、甲撑二氧去氧麻黄碱、甲氧乙心安、慢心律、甲苯吡、苯哒吗林、布鲁可待因、去甲替林、N-丙基阿义马林、奥丹亚龙、羟氢可待因、氟苯哌苯米、环己哌啶、奋乃静、苯乙双胍、异丙嗪、苯乙酰苯心安、萘心安、利螺环酮、鹰爪豆碱、甲硫哒嗪、噻吗心安、托莫西汀、托比色创、文拉法星、环氯噻醇和它们的可药用盐。
5.根据权利要求1的方法，其中CPY2D6抑制剂或它的可药用盐选自下组，包括：奎尼丁、萝芙辛、舍曲林、文拉法星、右美托咪定、曲喷尼胺，普利马塞嗪，羟嗪、卤福林坦、氯喹、吗氯贝胺和它们的可药用盐和圣·约翰麦芽汁或它的提取物或成分。
6.一种药物组合物包括：
(a)治疗有效量的药物，其在人体的主要清除机制是CYP2D6介导的氧化生物转化，或它的可药用盐。
(b)一定量的CYP2D6抑制剂或它的可药用盐，它对于治疗(a)中提到的治疗药物将治疗的紊乱或病症有效。
(c)可药用载体。
其中所述药物和所述CYP2D6抑制剂不是相同的化合物。
7.根据权利要求6的药物组合物，其中包含在所述药物组合物中的其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物或它的可药用盐选自下列组合物，包括：
(2S，3S)-2-苯基-3-(2-甲氧基-5-三氟甲氧-苯基)甲氧氨基-哌啶、苏尼帕；
(1S，2S)-1-(4-羟基苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇，和它的可药用盐。
8.根据权利要求6的药物组合物，其中其在人体的主要清除机制是CPY2D6介导的氧化生物转化的药物或它的可药用盐选自下组，该组包括：甲奎酚嗪、坦洛新、奥昔布宁、利托纳维、伊潘立酮、伊波加因、迪拉维丁、托特罗定、异丙嗪、匹莫齐特、伊匹斯汀、曲马朵、普鲁卡因胺、去氧麻黄碱、他莫昔芬；尼麦角林、氟西汀、烯丙心安、阿米夫胺、阿米替林、茚满丙二胺、溴法罗明、布图拉罗、肉桂苯哌嗪、氯丙咪嗪、可待因、异奎呱、去甲丙咪嗪、去甲西酞普兰、右芬氟拉明、右甲吗喃、二氢可待因、多拉斯琼、哌茴苯胺、乙基吗啡、哌氟酰胺、氟苯桂嗪、三氟戊肟胺、胍生、氟哌啶醇、二氢可待因酮、吲哌胺、丙咪嗪、麦普替林、甲氧苯丙胺、喘咳宁、甲撑二氧去氧麻黄碱、甲氧乙心安、慢心律、甲苯吡、苯哒吗林、布鲁可待因、去甲替林、N-丙基阿义马林、奥丹亚龙、羟氢可待因、氟苯哌苯米、环己哌啶、奋乃静、苯乙双胍、异丙嗪、苯乙酰苯心安、萘心安、利螺环酮、鹰爪豆碱、甲硫哒嗪、噻吗心安、托莫西汀、托比色创、文拉法星、环氯噻醇和它们的可药用盐。
9.根据权利要求6的药物组合物，其中CPY2D6抑制剂或它的可药用盐选自下组，包括：奎尼丁、萝芙辛、舍曲林、文拉法星、右美托咪定、曲喷尼胺，普利马噻嗪，羟嗪、卤福林坦、氯喹、吗氯贝胺和它们的可药用盐
10.根据权利要求6的药物组合物，其中的CPY2D6抑制剂是圣·约翰麦芽汁或它的提取物或成分。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101824467B (zh) * | 2009-12-29 | 2012-07-18 | 广州益善生物技术有限公司 | Cyp2d6基因突变检测液相芯片及检测方法 |
| CN105491885A (zh) * | 2013-03-07 | 2016-04-13 | 思想实验室有限责任公司 | 疼痛药物组合及其用途 |
| CN105491885B (zh) * | 2013-03-07 | 2018-09-25 | 思想实验室有限责任公司 | 疼痛药物组合及其用途 |
| CN106659789A (zh) * | 2014-08-14 | 2017-05-10 | 弗劳恩霍夫应用研究促进协会 | 疼痛治疗中的cyp2j2拮抗剂 |
| US11944613B2 (en) | 2014-08-14 | 2024-04-02 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | CYP2J2 antagonists in the treatment of pain |
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