Pharmacogenetics

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The pharmacogenetics deals with the influence of the different genetic makeup of patients on the effect of drugs . It allows predictions about the case-specific effect of a drug, which enables a dosage that is more closely adapted to the individual needs of a patient and helps avoid relative overdoses . The aim of the research is to break down the genetic variability of drug effects on a broad basis in order to use this knowledge for drug development and for the individualization of pharmacotherapy .

Basics

Living things metabolize foreign substances with the help of complex enzyme systems . These vary from individual to individual, since the genes from which they are derived occur in diverse, slightly to very different variants ( polymorphisms ). This results in a predictable restriction in activity up to complete failure in homozygous carriers of the respective genes.

Polymorphisms in transport proteins and drug target structures, such as receptors or intracellular molecules for signal transduction and gene regulation, are particularly influential and significantly more difficult to assess .

history

The first observation of a genetically justified the difference in the effect of a drug is from the 1950s and concerns for anesthesia related muscle relaxant succinylcholine : In rare cases (1: 3500 in people of white skin color) the duration of the muscle paralysis caused by succinylcholine is greatly extended because the enzyme pseudocholinesterase required to break down the drug is reduced.

The term pharmacogenetics was coined in 1959 by Friedrich Vogel ; Arno Motulsky was one of the co-founders of the subject .

state of research

Pharmacokinetics

Differences in the pharmacokinetics of a drug result in different concentrations of drugs and their metabolites in the blood and in the target tissues. A distinction is made here between the so-called phase I and phase II reactions . Phase I reactions contain minor modifications of the molecules ( oxidation and reduction reactions ), which in phase II reactions are supplemented by conjugations with water-soluble acid residues and thus the drugs are made accessible to the kidneys. Phase I reactions are mostly mediated by the family of cytochrome P450 enzymes (CYP); five of them alone (CYP3A4, CYP2D6, CYP2C19, CYP2C9 and CYP1A2) already implement the majority of hepatic drugs. For CYP2D6 and CYP2C19 gene variants are known that make their synthesis impossible. In the case of CYP2C9, the activity can be greatly reduced. CYP2D6 is about part of every fourth drug in the metabolism, including many antidepressants , antipsychotics , beta-adrenoceptor - antagonists , antiarrhythmics , antitussives and anti-emetics . A genetic deficiency leads to a significantly slower elimination from the body, which leads to a relative overdose with the correspondingly increased side effects . With CYP2D6 there is also very rarely a strongly increased activity due to a gene duplication on chromosome 22 , whereby CYP2D6 substrates are eliminated extremely quickly in homozygous carriers (ultrafast metabolizer, UM). Much more common, however, are heterozygous carriers (about 40% of the white population, intermediate metabolizers, IM) and carriers of two active CYP2D6 alleles (about 50%, normal metabolizers, extensive metabolizers, EM).

Important enzymes in drug or foreign substance metabolism with a hereditary polymorphism
enzyme Functional importance Frequency of homozygous genetic variants * Meaning u. a. for the following drugs
Phase I.
Cytochrome P450 (CYP) 1A2 high inducibility 46% Clozapine , Imipramine , Caffeine , Lidocaine , Paracetamol , Theophylline
CYP2A6 reduced activity 1 % Fadrazole , Halothane , Losigamon , Nicotine , Tegafur
CYP2B6 reduced activity 2% Bupropion , propofol
CYP2C8 reduced activity 1.7% Carbamazepine , cerivastatin , paclitaxel , pioglitazone , rosiglitazone , tolbutamide , verapamil , warfarin
CYP2C9 reduced activity 1-3% Celecoxib , Clopidogrel , Diclofenac , Fluvastatin , Glibenclamide , Ibuprofen , Lornoxicam , Losartan , Phenprocoumon , Phenytoin , Piroxicam , Sildenafil , Tenoxicam , Tolbutamide , Torasemide , Warfarin
CYP2C19 lack of activity 3% Diazepam , Lansoprazole , Omeprazole , Pantoprazole , Proguanil , Propranolol , Rabeprazole
CYP2D6 lack of activity / extremely high activity due to gene duplication 7% / 2-3% Ajmaline , Amitriptyline , Carvedilol , Codeine , Flecainide , Fluoxetine , Galanthamine , Haloperidol , Metoprolol , Mexiletine , Ondansetron , Propafenone , Tamoxifen , Timolol , Tropisetron
CYP3A4, CYP3A5, CYP3A7 Decreased activity expression of CYP3A7 in adults several mutations, some of them rare Quinidine , Cyclosporin A , Cortisol , Dapsone , Diltiazem , Erythromycin , Lidocaine, Midazolam , Nifedipine , Paclitaxel, Sildenafil , Simvastatin , Tacrolimus , Triazolam , Verapamil , Zolpidem
Flavin-dependent monooxygenase 3 (FMO3) decreased activity 9% Perazine , Sulindac , Albendazole , Benzydamine
Butyrylcholinesterase (BCHE) decreased activity 0.03% Succinylcholine
Dihydropyrimidine dehydrogenase (DPYD) decreased activity <1% 5-fluorouracil
Phase II
Arylamine-N-acetyltransferase 2 (NAT2) slow acetylators 55% Isoniazid , hydralazine , dapsone, sulfonamides , procainamide
Uridine Diphosphate Glucuronosyltransferase 1A1 (UGT1A1) reduced activity 10.9% Irinotecan
Glutathione-S-Transferase M1 (GSTM1) lack of activity 55% Disposition to bladder carcinoma
Catechol-O-methyltransferase (COMT) decreased activity 25% Estrogens , L-dopa , a-methyldopa , amphetamine
Thiopurine-S-methyltransferase (TPMT) lack of activity 0.3% Azathioprine , 6-mercaptopurine

* Frequency based on homozygous genotype among Caucasians. Table according to Kirchheiner, 2003.

Pharmacodynamics

The pharmacodynamics is influenced by differences in the target structures of the drugs, such as receptors or molecules of signal transduction, the effect and tolerability of drugs can vary. The β 2 -adrenoceptor , for example, (regulation of the vascular tone and the bronchodilation ) may, two point mutations  - Arg16Gly and Gln27Glu - have the effect of β2-sympathomimetic effect

Polymorphic genes that influence the drug action on the receptor or on the target structure
gene example Clinical impact
β 2 adrenoceptor (ADRB2) Albuterol , isoproterenol Different bronchodilation in certain alleles, tachyphylaxis, agonist-mediated desensitization and effect depending on genotype
Dopamine transporter (DAT1) L-dopa Occurrence of psychosis or dyskinesia
5-lipoxygenase (ALOX5) Zileuton No antiasthmatic activity in carriers of the tandem repeat promoter variant
Apolipoprotein E (APOE) Tacrine Only effective in ApoE4-negative patients with Alzheimer's disease
O-6-methylguanine-DNAMethyl-transferase (MGMT) Alkylating agents Promoter methylation and favorable therapeutic results in patients with gliomas
Voltage-dependent potassium channel type 2 (KCNE2) Sulfamethoxazole , procainamide, oxatomide drug-induced long QT syndrome in carriers of the variant
Glycoprotein IIIa (ITGB3) Platelet aggregation inhibitors ( ASA , abciximab ) Lower effectiveness in carriers of PLA2
Cholesteryl ester transfer protein (CETP) Pravastatin Slowed development of coronary arteriosclerosis only in carriers of B1B1
α-adducin (ADD1) Hydrochlorothiazide (HCT) With reduced sodium chloride and therapy with HCT, greater drop in blood pressure in carriers of 460Gly / Trp
Angiotensin Converting Enzyme (ACE) Enalaprilat Longer lasting and stronger effectiveness in carriers of the Ins / Ins genotype

Table according to Kirchheiner, 2003.

Clinical application

Diagnosis

A pharmacogenetic diagnostics provides independent of age the opportunity before the start of therapy clarify which drug, the individual characteristics of the metabolism of an individual patient is most suited in what dosage. The search for a suitable drug can be shortened considerably and the risk of unpleasant incidents can be reduced significantly. However, genotyping is currently only useful for therapies with drugs that have a narrow therapeutic range or a risk of severe adverse drug effects, which are known to be genetically determined. This applies, for example, to trastuzumab , a specific antibody against Her-2 receptors. This is only used for the treatment of breast cancer in the third of patients in whom overexpression of Her-2 receptors in the tumor tissue has been detected.

In 50 years of pharmacogenetic research, however, new findings have only found their way into clinical practice in the few cases in which clarification appeared to be sufficiently relevant for therapy planning and in clinical studies with an acceptable cost / benefit ratio actually led to significant improvements in quality of life and patient survival rates.

therapy

Recommendations for adapting therapy can be formulated in the form of dosage recommendations and treatment algorithms . Differences in pharmacokinetics that cause slower or accelerated degradation can usually be compensated for quite simply by increasing or decreasing the dose or by changing the intake interval according to the calculated blood plasma level. It becomes more difficult when several enzyme systems have to be taken into account that cannot be reliably estimated as a whole. With regard to genetic variables of the target structures, on the other hand, deriving therapy recommendations is fundamentally difficult, since in most cases only a probability statement is possible with regard to a changed response to drug administration. A sufficiently reliable prediction is possible if the drug effect is linked to the presence of a single variant, as is the case with trastuzumab. In most cases, however, it is not just various genes that determine the success of a drug therapy, but also other factors such as the specificity of the disease, individual characteristics of the patient (age, gender and body functions).

literature

Web links

Individual evidence

  1. ^ Vogel F. Modern problems in human genetics. Result Inn Med Kinderheilk 1959; 12: 52-125
  2. ^ Professor Arno Motulsky, recipient of the GfH Medal of Honor . German Society for Human Genetics