基于CYP2D6-和-CYP2C19基因型的抗抑郁药的量推荐

1、 个性化 方法: 这篇文章收录了 32种在Europe, Canada, and the United States市场上的抗抑郁药. 我们评估比较了了在 antidepressants among poor,intermediate, extensive and ultrarapid metabolizers. (药物动力学参数） Results: 14个抗抑郁药个抗抑郁药, 对于代谢类型为对于代谢类型为extensive, intermediate and poor metabolizers of either CYP2D6 or CYP2C19 给予不同的剂量给予不同的剂量. 对于三环类

2、抗抑郁药物对于三环类抗抑郁药物,或者是或者是CYP2D6的底物的底物 或者或者CYP2C19的底物的不良代的底物的不良代谢者，他的使用量降低了谢者，他的使用量降低了 ，而，而选择性选择性5羟色胺再羟色胺再吸收抑制剂吸收抑制剂在各个代谢类型人群中量的差异是很在各个代谢类型人群中量的差异是很小的。小的。 Conclusion: 我们基于基因型和蛋白型提供了初步的平均量建议. 这时应用新的遗传药理学考虑药物代谢容量差异来推荐药物的量.Introduction 已知遗传因素可以引起抗抑郁药物药效和不良反应上的差异，从而导致用药的个体差异。 无数研究团队进行了抗抑郁药物药物代谢酶基因多态性的研究。 尤其

3、很好的研究了CYP2D6 和 CYP2C19 遗传多态性对所有三环类和其他许多抗抑郁药物的药动力学影响的特征。 在高加索人群中，这两个酶的活性呈现双模状态。即分为广泛代谢者extensive metabolizers (EM) 和较少代谢者（或者不良代谢者）poor metabolizers (PM)。 在1970s,在研究司巴丁和异喹胍氧化时发现存在多态性- CYP2D6多态性。 CYP2C19 的多态性是在研究美芬妥英羟(基)化(作用) 多态性发现的。 CYP 多态性的频率已经在不同人群被调查，发现等位基因频率从本质上根本不同。 考虑不同种族间的差异是非常必要的。 抗抑郁药的临床药理学的多

4、态性的作用以前被综述过。 当你吃正常剂量的这些药物，CYP2D6 或 CYP2C19 底物的较少代谢者，比广泛代谢者更可能遭遇不良反应。 发生这些潜在问题的程度主要取决于各个CYP代谢酶对药物整个消除以及药物治疗指数的相对贡献。 （药物治疗指数是指药物的最低中毒浓度与最低有效浓度之比值!越高药物越安全！） CYP 多态性的分子遗传基础在一定程度上已经被阐明-这可以允许根据病人的药物代谢酶的蛋白型进行临床有用的预测。 治疗之前这样一个基因型被确定。 就可以作为一个预防不良反应的有用工具尤其，是对于治疗窗相对较窄的药物。 这个信息可以被应用于针对不同基因亚型的病人的平均使用剂量的提供。 反过来这也

5、可能提供治疗和药物经济学的利益。在将来的临床医生对于代谢者代谢状况的遗传分析可能将变得更常见。 基因分型有这样的好处：对于每个患者，一生只用进行一次，分析的成本比一天的住院费用低。 使用当前的技术，这样基因分型可能几个小时就操作完了。 类似于地高辛或者具有肾脏疾病的患者使用氨基糖甙类进行常规的剂量调整一样。或类似于小儿科各个特殊年龄组的剂量调整。需要特殊的建议来指导如何调整特殊代谢表型的药物剂量。 在高加索人群，对于 CYP2D6, 预测表型为不良代谢者的基因分型实验的总体敏感性比 99%更大一些，当检验常规的非活性的等位基因 (*3, *4, *5, *6, *7, *8,*16)。 考虑到

6、上述等位基因变异，虽然中间代谢者的分子遗传预测不是很精确，但是考虑到CYP2D6 等位基因 *2差异，鉴别中间代谢者的精密度可能会提高. 而对于 CYP2C19, 基因分型能鉴别出表型为不良代谢者在 93 和 100% 之间。 这篇综述的目的是基于药物代谢表型或基因型得到抗抑郁药物的剂量and, if such data were not available, to identify priorities for further clinical studies 因为没有进行每一个基因型的药效研究,所以我们假设相同的血药浓度意味着相同的药物作用。 基于多态药物代谢酶基因型的剂量调整伴随着活性代

7、谢物的存在。 所以我们提供几个研究活性代谢物对整个抗抑郁药物作用的评论者的参考。 抗抑郁药的消除可能被药物相互作用深深的影响。几篇综述都集中在抗抑郁药物代谢的抑制特性, 尤其详细地说明药物代谢的相互作用以及怎么进行避免。 为了进行最佳调整，对于药物的相互作用和其他因素如顺应性, 年龄或肝功损伤进行全面的了解，患者的临床检测和治疗药物检测在剂量优化上是必须的。 对于抗抑郁药物在剂量上发现的问题以前讨论过。不同类型的抑郁症需要不同的剂量这是没有多少可以令人信服的证据。 the dose requirements may be different compared to depression. 对于

8、三环类抗抑郁药，早期的经验具有严重的耐药性，导致使用起来有相当谨慎的剂量政策。 虽然某些被推荐的治疗药物检测的三环类抗抑郁药 (丙米嗪, 去甲替林)具有清晰的量效关系 然而, 一般情况下抗抑郁药物在量，血浆浓度和临床结果之间没有显示简单的关系. 较新的抗抑郁药物,尤其是选择性5羟色胺再吸收抑制剂 (SSRIs) 如 氟西汀,百忧解揭示单调的和重叠的抗抑郁和不良作用的量效曲线。 不幸的是,这些量效关系不包含药动学和药效学的遗传变异信息，这些信息可以解释给定相等剂量的病人之间的应答差异。 决定药物浓度的变异在遗传学上的评估可能确实改善了治疗作用，降低了耐受性的风险。Methods of data

9、analysisDefinitions and study inclusion criteria 我们考虑了所有关于抗抑郁药物的研究，除了关于锂的和抗精神病药和草药。 We reviewed only studies conducted in humans, either healthy volunteers or patients, in which the pharmacokinetic and/or pharmacodynamic药效(学)的parameters of antidepressants were measured, and where the polymorphic tra

10、its of CYP2C19 and CYP2D6 were determined Data from current Medline and Embase databases were used. We searched for any word combination of antidepressant* or antidepressive*with polymorph*, CYP*, cytochrome*,P450*, debrisoqu*胍喹啶, sparteine*司巴丁, dextromethorphan*右美沙芬 and mephenytoin*美芬妥英and the same

11、 search was carried out for all generic names通用名称of the specific antidepressants marketed in Japan, the United States and major European countries. Furthermore, manufacturers制造厂家of all antidepressants included in this study were asked to provide unpublished data未发表过的. Subjects with two active allele

12、s (*1, *2, *9, *10 and *17) were classified as extensive metabolizers, heterozygous杂合子的 carriers of one active and one deficient allele, thus carriers of one of the alleles *1, *2, *9, *10, *17 or other more rare active alleles combined with one of the alleles *3, *4, *5, *6, *7, *8 or other more ra

13、re completely deficient alleles were termed intermediate metabolizers (IM) in the present review。 The CYP polymorphisms can be distinguished区别 either by genotyping or by phenotyping methods. In studies using genotyping methods, subjects with three or more active alleles, i.e. carriers of CYP2D6 gene

14、 duplications基因重复(46) were classified as ultrarapid metabolizers (UM). because the subpopulation-specific clearance清除率of this group is between extensive and poor metabolizers. Subjects with two inactive alleles (*3, *4, *5, *6, *7, *8) were classified as PM. As an exception to this classification, i

15、n three studies from Asiatic populations carriers of two intermediately active alleles *9 and *10 of CYP2D6 were classified as IMs. Recent studies may even allow to distinguish the intermediate metabolizer group into further subgroups based on subtypes of allele *2, but no data existed with respect

16、to antidepressants. Much of the data on intermediate metabolizers in this review were based on phenotypically identified intermediate metabolizers with debrisoquine异喹胍, sparteine司巴丁or dextromethorphan右美沙芬for CYP2D6 or the mephenytoin美芬妥英 test for CYP2C19. We also included one study using quinidine奎尼

17、丁as an inhibitor of CYP2D6 to mimic模仿the poor metabolizer status.Consideration of active metabolites for genotype-based dose-recommendations Antidepressants undergo multiple biotransformations生物转化 in the liver, producing progressively more polar metabolites which can be eliminated more readily by th

18、e liver or the kidneys. If the antidepressant activity of a metabolite is comparable to that of the parent drug (usually demonstrated only in vitro) and if the metabolite exists in considerable concentrations in plasma, it was considered as a principle metabolite Such metabolites were taken into acc

19、ount in the dose recommendations by adding their plasma concentrations to those of the parent drug. We did not consider active metabolites which are formed in minor quantities(少量）, have short half-lives, or are substantially less active than the parent drug (Table 1)。 Our classification is not compl

20、ete, but includes the relevant metabolites which have been studied clinically in this context. These classifications are of a preliminary nature, as they are based mainly on experimental data on receptor or transporter binding。 In some cases, such as described below for nortriptyline去甲替林, different

21、approaches gave incongruent不一致的results. Besides their intrinsic内在的potency, the clinical effects of metabolites depend on their volume of distribution and rate of diffusion扩散into the central nervous system (CNS). The lipid solubility of most metabolites is decreased compared to the parent drug which

22、may result in a smaller volume of distribution and a reduced ability to pass the bloodbrain barrier.Handling of pharmacokinetic data We have based the dose recommendations on pharmacokinetic parameters which are generally linear and thus proportional to dose such as area under the curve (AUC), total

23、 clearance (Cl) and steady-state trough levels (Css)， because this method of dose adjustment may be sufficiently accurate in most cases。 such as clomipramine氯丙咪嗪, desipramine去甲丙咪嗪,imipramine丙米嗪, moclobemide吗氯贝胺, trimipramine三甲丙咪嗪,paroxetine帕罗西, fluvoxamine氟甲沙明and possibly fluoxetine氟西汀,the genotype-

24、based dose adjustments are in theory specific for the doses tested in the studies. Furthermore, because the relative contribution of specific cytochrome P450 enzymes may depend on the substrate concentration, the recommendations may not be valid合格的 far outside the dose range of the reviewed studies。

25、 Studies which provided only the ratios between the concentrations of the parent drug and its metabolite and not the actual plasma concentration data could not serve for quantitative dose adjustments. Since such metabolic ratios provide information about the cytochrome enzymes involved in the metabo

26、lism, we have included them in the qualitative定性的Table 2. Although we recorded covariables可协变的such as gender, age, ethnicity, dose level and tobacco smoking, the limited availability of such data made it impossible to consider these variables systematically in the dose recommendations. When the diff

27、erences in pharmacokinetic data between PMs and EMs, or IMs and EMs, were statistically significant, dose recommendations were deduced推论by calculating the ratios of AUC or Css between PMs and EMs and, if available, between IMs and EMs. 如果几个药物进行了几个研究，我们通过计算加权平均值概括 AUCs 或者 Css by calculating the weigh

28、ted mean加权平均值from the various studies. 这是氯丙咪嗪，去甲丙咪嗪单剂量和多剂量研究, 氟西汀(studies providing data on FLU and NOR-FLU) ，氟甲沙明, 丙米嗪关于CYP2D6和 CYP2C19, 单剂量的去甲替林和文拉法辛研究包括只有一个不良反应代谢者, 但是剂量推荐可能被仔细考虑。 我们区别单剂量和达稳态血药浓度的剂量. 药物的推荐量被分别计算，治疗开始（单剂量研究结果）和多剂量治疗（主要不总是在稳态） 虽然如果在说明书里面得到数据，但是可能从表格和图标里面得到，或者从原始数据计算得到. 测量的单位被统一到mmo

29、l ,L和 h, 和清除率被统一到L N hx1 N kgx1. 如果If individual body weights were not available, we applied a unified weight of 70 kg. Average dose recommendations (DAv) provided in manufacturers information may be considered as the pragmatic ,实用的results of large-scale studies performed within genetically遗传上地mixed

30、 populations. These DAv may thus be further considered as the weighted means from a Caucasian population with 10% genetically defined PMs, 40% IMs and 50% EMs (rounded data for CYP2D6 (15) or DAv =（0.1DPM + 0.4DIM+ 0.5DEM with DPM, DIM and DEM representing the doses which might have been recommended

31、 for the subpopulations poor metabolizers, intermediate metabolizers and extensive metabolizers, respectively. Based on the reviewed studies, we calculated the ratio of the parameters in PMs to EMs and, if available, IMs to EMs or UMs to EMs, in a manner similar to that of other reviews. Dose recomm

32、endations were rounded to the nearest number which can be divided by 10. To calculate the dose for each genotype, we proceeded as follows: By substituting equation (2) and (3) into equation (1), these relations can be transformed to percent adjustment compared with the average dose DAv (100%) for th

33、e EMs: For CYP2C19, these calculations were based on the genotype frequencies of 3% PMs, 20% IMs and 77% EMs. Phenotypically defined EMs also include subjects with one active allele which can be identified only by genotypical methods. We realize that with the approximation explained above one might

34、even underestimate the difference between EMs and PMs when using data from phenotyping studies. Often, no data were available on antidepressant pharmacokinetics in IMs and UMs. When no information for IMs was provided, we estimated the dose for IMs as the mean of PM and EM, owing to the fact that re

35、cent studies indicated a roughly proportional比例的genedose relationship for genetically polymorphic enzymes. Since genetically遗传上地identified UMs are rare (less than 3% in most Caucasian populations), data for this genotype group were rarely available, and we felt unjustified in extrapolating延伸beyond t

36、he measured range between PM and EM.Results and discussion Table 2 presents a qualitative summary of all available data on the impact of drug metabolic polymorphisms in the biotransformation of antidepressants. There was no clinical study on the impact of CYP2C9 polymorphisms (111) on the metabolism

37、 of antidepressants and the functional role of the recently discovered genetically identified CYP1A2 and CYP3A4 polymorphisms For 11 of the 32 drugs included, no studies on CYP enzyme-specific metabolism were found. Fourteen of the remaining 21 drugs were predominantly主要地metabolized by CYP2D6 and/or

38、 CYP2C19 The drugs primarily主要地metabolized by CYP2D6 are desipramine, fluoxetine, fluvoxamine, maprotiline, mianserin, nortriptyline,paroxetine and venlafaxine. Elimination was found to be catalysed primarily by CYP2C19 in case of moclobemide, trimipramine and citalopram and both enzymes were involv

39、ed in amitriptyline,clomipramine, and imipramine metabolism. For these 14 polymorphically metabolized drugs, we attempted to give practical dose recommendations for each genotype. Seven antidepressants are metabolized primarily by enzymes other than除外CYP2D6 and CYP2C19. Bupropion丁氨苯丙酮is metabolized

40、via CYP2B6, whereas mirtazapine米尔塔扎平, nefazodone萘法唑酮, sertralineand trazodone are probably metabolized to a large extent by CYP3A4, an enzyme for which genetically defined poor or ultrarapid metabolizers have not been identified. Tables 3 and 4 present all those studies which could be used to derive

41、 genotype-based dose recommendations by the methods explained in the method section. If the drug is metabolized to principle active metabolites, studies with data on both, parent drug and metabolite, are presented in the table. Preliminary dose recommendations given in Table 5, however, were deduced

42、 only from studies with data on parent substance plus principle metabolite (AT, CMI, FLU, MIA). If available,AUC data are given; otherwise否则, trough levels are presented. Dosage by single or multiple-dosing is also differentiated in the table (S versus M). The tables also present the number of poor,

43、 extensive or intermediate metabolizers in each study. In Table 3, pharmacokinetic parameters are shown, underlying dose recommendations concerning the CYP2D6 gene polymorphisms, in Table 4 it was performed analogous for CYP2C19. Table 5 provides dose recommendations for drugs primarily metabolized

44、by CYP2D6 or CYP2C19 with reference to the average dose advised by manufacturers dosage guidelines. The table is subdivided into dose recommendations for multiple-dosing (M) and for the initial dose of treatment (S). If only minor differences between PMs and EMs exist, these may be relevant for eval

45、uation of efficacy or adverse events in large populations and in large clinical drug trials. In daily medical practice, however, these differences may be neglected. For desipramine and imipramine the doses administered in the studies did not correspond to usual therapeutic doses in antidepressant tr

46、eatment. For these drugs, further studies should be performed using clinically administered doses. Few studies exist which evaluate differences in efficacy in relation to genotype because most studies were pharmacokinetically orientated向东and often carried out in healthy volunteers or the studies sim

47、ply entailed使人承担very small samples. Table 6 presents five of all 54 studies which provide data on efficacy. Except for one study, no statistically significant differences were found between the groups. Several studies reported an incidence of adverse drug reactions which was higher in poor metaboliz

48、ers (with high drug concentrations) than in extensive metabolizers. However, only five of the 54 studies provided explicit data. In all studies, the number of PMs was small, resulting in a low statistical power. Table 7 presents the studies which evaluate genotype- specific differences in adverse dr

49、ug effects. The following section summarizes essential data for pharmacogenetically based dose adjustments; the list of drugs is in alphabetical order.Amitriptyline阿米替林 AT is demethylated to the principle active metabolite nortriptyline (NT). Demethylation of AT is mediated by CYP2C19 and by other C

50、YP enzymes, including CYP2D6, as well as by smoking-induced enzymes such as CYP1A2. According to in-vitro data, variability in the activities of CYP2C9 and CYP3A4 may additionally contribute to the pharmacokinetic variability of amitriptyline Hydroxylation of AT is catalysed primarily by CYP2D6 in v

51、ivo. The pharmacological药理学的activity of the hydroxylated metabolites is substantially lower than that of ATand NT . Genotype-based dose adjustments were calculated on the basis of the sum of AT and NT.Dose recommendations Based on two studies, PMs of CYP2D6 ought to receive about 50% and EMs about 1

52、20% of the manufacturers recommended dose (Dav). The impact of the CYP2C19 polymorphism requires further studies;according to one study, PMs of CYP2C19 should receive 60% and EMs 110% of the of the average dose. The monocyclic antidepressant BUP, for which the mechanism of action is still controvers

53、ially discussed, is metabolized by oxidative side-chain cleavage to the active hydroxy-bupropion, threohydrobupropion and the inactive erythrohydro-bupropion. According to in vitro data, hydroxylation of bupropion is mediated by CYP2B6 (120). Clinical studies suggested that CYP2D6 is not involved bu

54、t the carbamazepine酰胺咪嗪inducible enzymes诱导酶, like CYP3A4 may be involved in BUP biotransformation. No dose recommendations can be given.Current limitations of CYP genotype-based dose adjustmentsand further research directions We reviewed the literature for 32 currently marketed antidepressants used

55、in Europe, the United States, and Canada with respect to the clinical relevance of genetic polymorphisms in drug metabolism. A total number of 54 studies was found for CYP2D6 and CYP2C19, which both show well-defined gene polymorphisms Most studies discriminated between PMs and EMs, but seldom inclu

56、ded data on IMs and UMs. It was our objective to transform these qualitative recommendations to distinct dose adjustments according to genotype. Our reasoning was as follows: as long as we cannot provide relatively precise dose recommendations, the concept of genotype- based optimization of individu

57、al drug treatment cannot be applied by clinicians, and cannot be proven in prospective studies. Some drugs have metabolites which contribute substantially to the overall antidepressive effect which we called principle metabolites. We expected the same antidepressive effects for individuals with high

58、 levels of the parent drug and low levels of a principle active metabolite as for individuals demonstrating the inverse conditions, and thus provided dose recommendations based on the sum of the plasma concentrations of the parent drug and its principle metabolite (Table 5). However, even if the dru

59、g and its metabolites have similar anti-depressive activity such as clomipramine and desmethylclomipramine or amitriptyline and nortriptyline, the therapeutic properties and adverse effects may differ depending on the drug-to-metabolite ratio even if the sum of parent drug and metabolite is similar

60、in poor and extensive metabolizers: the therapeutic role of active metabolites is often not well defined, since data are generally derived from in-vitro studies measuring reuptake inhibition or receptor binding. In vivo, there are several uncertainties: e.g. penetration of the metabolites into the b