Chapter 3
ADME Pharmacogenetics and Its Impact on Drug–Drug Interactions
Abstract
- CYP酶CYP2B6, CYP2C9, CYP2C19, and CYP2D6和转运体 ABCB1 and OAT1B1具有genetic polymorphisms, 约占人群的1%
3.1 Introduction
- pharmacogenetics的关注重点已由最开始的药物代谢酶(M)，扩展到影响ADE的膜转运体
- Genetic variants not only determine to which extent a drug is metabolized, taken up or excreted by ADME genes, but they also influence the various mechanisms of how two or more drugs interact with the resulting protein.
- 某些基因型会直接影响the induction potential of a drug; 通常酶活性的基线水平越低，被诱导剂诱导的越高，但如果absent or low baseline activity是null alleles或其他遗传因素导致的话，就可能会出现不诱导的现象；
- 遗传多态性对药物代谢酶和转运体对drug exposure的影响的研究很多，直到最近才有少数研究者关注是否这些polymorphisms会改变inter individual susceptibility to or the degree of induction or inhibition.
3.1.1 CYP450s
- CYP450酶responsible for about 75% phase I代谢；
- 有40%CYPs are genetically polymorphic: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5;
- Genetic variation会导致病人或者extensive metabolizers(EMs), poor metabolizers(PM2), or intermediate metabolizers (IMs) of drugs; CYP2D6由于gene amplifications 而被认为是ultra rapid metabolizer phenotype (UM)
- 关于CYP代谢酶遗传多态性的详细综述： Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526.
CYP2B6
- highly polymorphic and is subject to high inter individual variability in expression and activity
- 最常见variant allele, CYP2B6*6, 由两个single nucleotide polymorphisms (SNPs)构成，c.516G>T(Q172H)和c.785A>G(K262R), 突变频率在12~49%
- 增高HIV-infected病人血中efavirenz, nevirapine-related neurotoxicity；这与CYP2B6*6的活性较低是一致的
- c.785A>G(CYP2B6*4)突变后，活性在Caucasian(4%)和Asian(7%)人中会增强
- African人群中存在null allele lacking的情况，CYP2B6*16，导致完全没有活性
- Importantly, this genotype effect may be inhibitor-specific
CYP2C9
- 至今，已报道30种CYP2C) allelic variants located within the coding region
- *2和*3 alleles在Caucasian人中约占25%，而在黑色人种和Asian人中less prevalent
- 体外试验显示，*2和*3 alleles与intrinsic clearance的显著reductions有关；*3受影响比*2更大，某些底物的活性会被减少90%
- 大量临床试验显示*2和*3与药物的ADR有关，例如 hypoglycemia from oral antidiabetic drugs, gastrointestinal bleeding from NSAIDs, and serious bleeding from warfarin treatment。
CYP2C19
- CYP2C19 PM phenotype results from two null alleles,导致缺失CYP2C19功能蛋白
- 约2-7%的white and black，以及up to 30%的Asians是CYP2C19 PMs.
- 最常见null alleles是CYP2C19*2, 主要出现在Caucasians，和CYP2C19*3，主要出现在Asians。
- 最近发现CYP2C19*17与increased substrate turnover (UM)有关，但是具体机制不明。
- 2C19 PM受益于omeprazole的高血药浓度，加速ulcer healing, 但由于不能bioactivation of 前药clopidogrel会suffer from lower anti platelet effect
CYP3A4/5
- CYP3A subfamily members是人类的最重要的药物代谢酶，参与约40%最常prescribed药物的代谢
- CYP3A的表达和功能highly variable
- little evidence for a relevant contribution of CYP3A4 gene polymorphisms in deterring CYP3A4 activity
- higher incidence of inactive CYP3A5*3 allele in Caucasians(85-89%) vs African Americans(30-50%)
- CYP3A*6, *7都没有功能活性，发现于African origin的受试者中
CYP3D6
- 虽然2D6的表达量仅占2-5%，但是前200名处方药物中，有15%是由2D6代谢的。
- 除了野生型的CYP2D7*1, 已鉴定超过80种variant alleles
- CYP2D6*1, *2, *33, *35具有正常酶活性；CYP2D6*3, *4, *6, *7, *8 没有活性；CYP2D6*9, *17, *41的活性降低
3.2 Drug Transporters
- a comprehensive overview on transporter pharmacogenomics: Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics 9:597–624.
ABCB1 (P-gp) Polymorphisms and Drug Interactions
- To date, more than 100 variants have been identified in the ABCB1 (MDR1) gene
- synonymous SNP in exon 26 (c.3435C>T) 引起广泛兴趣，由于其与P-gp活性和功能的改变有关
- 鲜有研究解决了P-gp抑制剂或诱导剂与 the ABCB1 genotype-based interaction，是因为in vitro assays are experimentally and technically elaborative and of limited availability,
- 此外，许多P-gp底物和抑制剂也是CYP3A的底物和抑制剂，在临床上难以区分P-gp转运抑制与CYP3A介导的代谢
- Dipyridamole通过提高intestinal absorption，提高digoxin的血药浓度；但具体机制尚有争论
- 体外实验显示P-gp也影响药物的intrahepatocyte concentrations and metabolic rates
3.3 Drug Uptake Transporters
OATP Polymorphisms and Drug Interactions
- OATP1B1 mediates the uptake on the sinusoidal membrane (窦状小管) of human liver
- Of more than 40 sequence variations, 17 nonsynonymous (change of an amino acid) have been identified in the SLCO1B1 gene encoding OATP1B1
- the nonsynonymous c.521T>C (Val174Ala) SNP与转运体体内外活性降低有关
- 尤其重要的是the 174Ala-encoding ∗5, ∗15, and ∗17 alleles for the hepatic uptake and disposition of water-soluble 他汀类药物 (pravastatin, pitavastatin, rosuvastatin, atorvastatin, and simvastatin acid)
- 黄芩苷诱导OATP1B1，提高*15突变者体内的rosuvastatin的血药浓度
OCT Polymorphisms and Drug Interactions
- Currently, 认为三种OCTs与药物转运有关
- 研究显示SLC22A1的几个polymorphisms会影响OCT1的体外转运功能和metformin的体内暴露和glucose-lowering effects; 它们对drug interactions的影响仍不明确
- More than 40 genetic variations in the OCT2 encoding SLC22A2 gene have been reported
- 中国健康受试者身上发现，cimetidine对OCT2-mediated的肾清楚metformin的抑制效应与polymorphism有关，仅在c.808∗TT genotype上可检测到
3.4 Clinical Relevance of Pharmacogenetics for DDI
- 关于polymorphisms是否会改变个体的敏感性(susceptibility) 或受诱导或抑制的程度的研究很少
- 除少数特例外，相比于PM，大部分inhibitory drug interaction发生在EM中，其抑制的程度可通过相关CYP酶baseline代谢活性的genotyping来预测
- 相同的concept也适用于转运体蛋白；
- Genetic polymorphisms具有重要临床意义的前提条件：
- 具有low therapeutic index
- 血浆药物浓度与临床终点或药效或浓度相关的副作用间存在清晰的关联
- Metabolism or transport is mainly via a single pathway mediated by the polymorphism.
3.4.1 Implications for Drug Treatment
- drug interaction的程度越大，越有可能导致toxicity or therapeutic failure
- PK的改变不一定影起PD的改变，但一些常用药物exposure的提高确实改变了PD. 例如，diphendydramine与metoprolol共同给EMs服用，不仅显著改变PK，也会延长negative chronotropic and inotropic effects. 这样的效应在PMs中未发现
- 为了治疗comorbid symptoms，antipsychotics和antidepressants常需同时服用。Antidepressants，例如paroxetine和fluoxetine是CYP2D6的potent inhibiors，而2D6又负责许多antipsychotic medications的代谢，这些抗精神药物大多具有很窄的治疗窗。研究显示此种DDI会提高锥体束外综合征（extrapyramidal symptoms）的发生频率，或使其恶化; more likely to be seen in EMs.
- it is worthwhile to note that enzyme activity also varies broadly among EMs.
- 许多药物涉及多个代谢途径和转运体，should be viewed and evaluated as an integrative system rather than single components.
3.4.2 Implications for Drug Development
- 虽然it is logical that Ems发生DDI的程度更大些，但是只有少数药物在研发过程中区分EMs和PMs
- 主要为PMs的DI研究会不能发现inhibitory effects导致没有DDI的错误结论
- A properly designed DDI study应根据受试者的genotype来筛选，排除PMs，纳入various EM genotypes;
- 由于DDI试验仅涉及某些model substrates, inhibitors, or inducers，在generalize 结论时应加倍小心
- 如果IND涉及polymorphic protein代谢或转运，与临床相关性>25%，就应该把此pathway加入到药物开发中和决策制定过程中
3.5 Conclusions
- 理解遗传因素对代谢、转运和DDI的影响 is critical to the benefit/risk assessment of a drug
3.5.1 WEB-Based Scientific Resources
- PharmGkb. The Pharmacogenetics and Pharmacogenomics Knowledge Base. Available from: http://www.pharmgkb.org/
- Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table.http://medicine.iupui.edu/flockhart/table.htm