Lecture 9 - Pharmacogenetics & Pharmacogenomics pt1

• Genetic factors


  • Genetic variation between individuals can lead to differences in drug response
  • This can include hereditary mutations, acquired mutations, single nucleotide polymorphisms (SNPs), and chromosome structural variations
  • These variations can affect the pharmacokinetics and pharmacodynamics of drugs, leading to altered drug metabolism, absorption, distribution, and elimination, as well as differences in drug receptors and downstream signaling pathways
• Ethnicity


  • Different ethnic groups may have distinct genetic variations that influence drug response
  • For example, variations in cytochrome P450 enzymes, which metabolize a large percentage of drugs, can differ between ethnicities and impact drug metabolism
• Age


  • Age-related changes in drug metabolism and response can occur due to physiological changes in the body, such as liver and kidney function, as well as changes in drug receptor expression and sensitivity
• Pregnancy


  • Pregnancy can alter drug metabolism and response due to hormonal changes and physiological adaptations in the body
  • This can impact drug efficacy and safety for both the mother and the developing fetus
• Co-morbidities


  • Individuals with co-existing medical conditions may have altered drug responses due to interactions between the disease and the drug, as well as potential changes in drug metabolism and clearance
• Other drugs


  • Concurrent use of multiple medications can lead to drug-drug interactions, affecting the metabolism and efficacy of each drug
  • This can result in varied responses to the same drug when used in combination with other medications
• Other reasons


  • Other factors, such as lifestyle, diet, environmental exposures, and individual differences in drug absorption and distribution, can also contribute to differences in drug response among individuals
• Pharmacogenetics


  • Study of how differences in single genes can cause variation in a person's response to drugs
  • Focuses on specific genetic variations that affect drug metabolism, absorption, distribution, and excretion
  • Examines how individual genetic makeup can influence drug efficacy and side effects
  • Investigates hereditary and acquired mutations that can impact drug responses
• Examples of pharmacogenetics

  • Glucose 6-phosphate dehydrogenase deficiency
  • Drug acetylation deficiency
  • Cholinesterase deficiency
  • TPMT deficiency
  • Aminoglycoside-induced ototoxicity
• Pharmacogenomics


  • Genome-wide assessment of the causes of variation in a person's response to drugs
  • Explores how variations in the entire genome can affect drug responses, including alterations in pharmacokinetics and pharmacodynamics
  • Aims to identify the genetic basis of inter-individual variation in drug response to improve clinical outcomes
  • Utilises advanced technologies such as the human genome project and next-generation sequencing to study the genetic factors influencing drug responses
• Historical origins of pharmacogenetics include single gene deficiencies causing variation in drug responses
• Types of genetic variation between individuals

  • Hereditary mutations
  • Acquired mutations
  • Single nucleotide polymorphisms (SNPs)
  • Chromosome structural variation/abnormality
  • Polymorphisms in cytochrome P450 enzymes
• Hereditary mutations


  • Mutation presents in all cells of the body for the entire life
  • Can lead to altered amino acids or premature STOP codons
  • May alter gene expression, such as promoter transcription factor binding sites
• Acquired mutations


  • Occurs in a mosaic pattern of normal and mutant cells
  • Can lead to larger changes including deletions, duplications, inversions, and translocations
• Single nucleotide polymorphisms (SNPs)


  • Individual variations in a single nucleotide within the DNA sequence
  • Can occur in coding and non-coding regions of the genome
  • May alter gene expression, protein structure, or function
• Chromosome structural variation/abnormality


  • Involves the insertion or deletion of 1 nucleotide to thousands of nucleotides
  • Can cause frameshift mutations or premature STOP codons
• Polymorphisms in cytochrome P450 enzymes


  • Extensive genetic polymorphisms in the cytochrome P450 superfamily of enzymes
  • Individual cytochrome P450s show substantial polymorphisms, with variations in substrate binding cavities and numerous single nucleotide polymorphisms (SNPs) affecting enzyme activity
• Specific examples of how genetic variation alters drug responses

  • Glucose 6-phosphate dehydrogenase deficiency
  • Drug acetylation deficiency
  • Cholinesterase deficiency
  • TPMT deficiency
  • Genetic variation in cytochrome P450 enzymes
• Glucose 6-phosphate dehydrogenase deficiency


  • Mutations in the G6PD gene can lead to reduced enzyme activity, causing a lack of reducing power in red blood cells
  • This deficiency can result in hemolytic anaemia after treatment with certain drugs, such as primaquine, due to oxidative stress and rbc lysis
  • G6PD deficiency is most common in populations with a history of malaria (African, Mediterranean and Southeast Asian descent), as it provides protection against the infection by disrupting the plasmodium growth
• Drug acetylation deficiency


  • Variants in the N- acetyltransferase 2 (NAT2) enzyme can lead to slow or fast acetylation of drugs like isoniazid
  • Slow acetylators may experience higher levels of drug toxicity, while fast acetylators may require higher doses to achieve therapeutics effects
  • This variation can result in bimodal plasma drug distribution and increased risk of isoniazid toxicity, particularly in certain ethnic groups, with around 50% of Caucasians and over 80% of Egyptians being fast acetylators
• Cholinesterase deficiency


  • Abnormal plasma cholinesterase activity can lead to prolonged paralysis afyer administration of succinylcholine, a neuromuscular blocking agent used in anaesthesia
  • Individuals with this deficiency may experience muscle relaxation and short term paralysis, lasting up to 10hrs, due to the failure to inactivate succinylcholine
• TPMT deficiency


  • Genetic polymorphisms in the TPMT gene can lead to variations in enzyme activity, resulting in different levels of thiopurine methyltransferase
  • Individuals with low TPMT activity may experience prolonged high levels of thiopurine drugs, leading to bone marrow suppression, while those with high TPMT activity may require dose adjustments for effective treatment of cancers or inflammatory disease
  • This variation highlights the narrow therapeutic range mercaptopurine and the need for personalised dosing based on TPMT activity levels
• Genetic variation in cytochrome P450 enzymes


  • Cytochrome P450 enzymes are a diverse superfamily of enzymes that metabolize approximately 75% of drugs and can either cause drug elimination or pro-drug activation
  • There are 57 human cytochrome P450 enzymes, organized into 18 families and 43 subfamilies, with many individual enzymes showing extensive polymorphism in the human population
  • Individual cytochrome P450s metabolize 10s to 100s of known drugs, and collectively, CYPs 1-3 metabolize 100s to 1000s of drugs
  • The number of known drugs metabolized by a given CYP can vary, with CYP2D6 metabolizing over 200 drugs
  • Polymorphisms in cytochrome P450 enzymes can lead to substantial variability in drug metabolism and response in different individuals
  • The polymorphisms in cytochrome P450 enzymes can concentrate in the substrate binding cavity, affecting the enzyme's activity and its ability to metabolize specific drugs
  • The genetic basis of variation in cytochrome P450 enzymes is due to the presence of multiple different alleles (gene variants) at the same locus in the population, leading to polymorphisms in these enzymes