Adverse Psychiatric Reactions Information Link
Promoting awareness of medicines that can harm mental health

Pharmacogenetics

Nuffield Biotethics held a meeting in 2003  at which it was stated that 50 of the most commonly prescribed drugs including cardiac and psychotropics, use a genetic enzyme in the Cytochrome P450 group know as CYP 2D6

The Pressing Need for Pharmacogenetics - Personalised Medicine

Talk by NHS Chair of Pharmacogenetics Professor Munir Pirmohamed at APRIL's 2008 conference

 

Genetics of Adverse Drug Reactions Abstract

  1. Chuang-Wei Wang1,
  2. Wen-Hung Chung1,
  3. Shuen-Iu Hung2

Published Online: 16 JAN 2017

DOI: 10.1002/9780470015902.a0024914

Adverse drug reactions (ADRs) remain a common and a major problem in healthcare. Many kinds of ADRs are predictable, dose-dependent and associated with the pharmacodynamic and pharmacokinetic of drugs. However, some are unpredictable, dose-independent and termed as idiosyncratic reactions. A number of recent studies have demonstrated that ADRs possess strong genetic predisposition, and the associated risk variants include HLA alleles [e.g. HLA-B*15:02 for carbamazepine-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), HLA-B*58:01 for allopurinol-induced SJS/TEN and HLA-B*57:01 for abacavir hypersensitivity], drug-metabolising enzymes (e.g. CYP2C9*3 for phenytoin-induced severe cutaneous adverse reactions and NUDP15 missense variants for thiopurine-induced leukopenia) and drug transporters (e.g. SLCO1B1 variants for statin-induced myopathy). These findings not only give insights into the pathogenesis of ADRs but also lead to the development of useful tests to reduce the incidences of ADRs.

Key Concepts

  • ADRs possess strong genetic predisposition, and the identified important risk factors include genes encoding human leukocyte antigens (HLA), drug-metabolising enzymes and drug transporters.
  • The human HLA alleles are highly polymorphic and associated with different types of ADRs, including cutaneous adverse reactions and drug-induced liver injury. The association has characteristics of drug-, ethnic- and phenotype-specificity.
  • The human HLA alleles exhibit strong association with severe cutaneous adverse reactions, for example, HLA-B*15:02 and carbamazepine-induced SJS/TEN, HLA-B*58:01 and allopurinol-induced SJS/TEN/DRESS and HLA-B*57:01 and abacavir hypersensitivity.
  • Polymorphisms of cytochromes P450 (e.g. CYP2D6, CYP2C9 and CYP2C19) and other drug-metabolising enzymes (e.g. glucose-6-phosphate dehydrogenase and nucleoside diphosphate linked moiety X-type motif 15) can cause defective or altered enzyme activity, and are associated with different kinds of ADRs.
  • The genetic alterations of drug transporters (e.g. ATP-binding cassette (ABC) and solute carrier (SLC) transporters) are also linked to ADRs.
  • The epigenetic effects on drug-metabolising enzymes and drug transporters may also contribute to the individual susceptibility to ADRs.
  • Implementation of the genetic screen before drug prescription has been applied in clinical practice, and these pharmacogenetic tests show efficacy for preventing ADRs.

    Keywords:

  • adverse drug reactions;
  • CYP;
  • drug-metabolising enzymes;
  • drug transporters;
  • genetics;
  • HLA;
  • pharmacogenomics

 

Pharmacogenetics and the concept of individualized medicine. Abstract

Shastry BS1.

Abstract

Adverse drug reaction in patients causes more than 2 million hospitalizations including 100,000 deaths per year in the United States. This adverse drug reaction could be due to multiple factors such as disease determinants, environmental and genetic factors. In order to improve the efficacy and safety and to understand the disposition and clinical consequences of drugs, two rapidly developing fields--pharmacogenetics (focus is on single genes) and pharmacogenomics (focus is on many genes)--have undertaken studies on the genetic personalization of drug response. This is because many drug responses appear to be genetically determined and the relationship between genotype and drug response may have a very valuable diagnostic value. Identification and characterization of a large number of genetic polymorphisms (biomarkers) in drug metabolizing enzymes and drug transporters in an ethnically diverse group of individuals may provide substantial knowledge about the mechanisms of inter-individual differences in drug response. However, progress in understanding complex diseases, its negative psychosocial consequences, violation of privacy or discrimination, associated cost and availability and its complexity (extensive geographic variations in genes) may become potential barriers in incorporating this pharmacogenetic data in risk assessment and treatment decisions. In addition, it requires increased enthusiasm and education in the clinical community and an understanding of pharmacogenetics itself by the lay public. Although individualized medications remain as a challenge for the future, the pharmacogenetic approach in drug development should be still continued. If it becomes a reality, it delivers benefits to improve public health and allow genetically subgroup diseases thereby avoiding adverse drug reactions (by knowing in advance who should be treated with what drug and how).

PMID:
16302022
DOI:
10.1038/sj.tpj.6500338
[Indexed for MEDLINE]

 

2004;4(13):1411-21.

Güzey C1, Spigset O.

Abstract

During the last decades, the rapid development in molecular biology has contributed to the understanding of genetic factors underlying many adverse drug reactions. Until recently, most research in this area has focused on genes coding for drug-metabolizing enzymes. Inactivating mutations have been found in genes coding for enzymes belonging to the cytochrome P-450 system, which is the major system for drug metabolism in humans, but also in genes coding for other enzymes. Subjects with a lack of functional activity in these enzymes should be treated with very low doses of drugs metabolized by the same enzyme in order to avoid excessive drug levels and thereby toxic effects. In the last years, increasing attention has been directed towards genes coding for drug targets. Hitherto, most studies have been carried out on single genes known to be or assumed to be functionally related to a given adverse drug reaction. Another approach, which may become more common in the future, is testing for complex single nucleotide polymorphism patterns that may be associated with adverse drug reactions, although the functional relationship between them may be completely unknown. Due to the influence of non-genetic factors in the development of adverse drug reactions, the association between a specific genotype and an adverse drug reaction will always be lower than 100%. Therefore, there is a need for prospective large-scale studies in order to elucidate the extent of environmental influences on the adverse drug reactions for which a genetic basis has been suggested. Despite these obstacles, pharmacogenetic testing will hopefully in the future identify at least some clear-cut situations where a drug should be avoided in certain individuals in order to reduce the risk of adverse drug reactions.

PMID:
15379654
[Indexed for MEDLINE]

 

Powered by Charity Edit