BMS3021 Lecture Notes - Lecture 7: Streptokinase, Drug Discovery, Salbutamol
30 May 2018
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Week 3. Pharmacogenetics, Drug development from
laboratory to clinic and Case study – Agomelatine
PHARMACOGENETICS
• Pharmacogenetics: is the study of inter-individual variation in DNA sequence related to
pharmacokinetics or pharmacodynamics
• Target of a drug is a protein, protein is from a gene and genes are different in every individual
• Inter-individual variability:
o For all major classes of drugs, a substantial proportion of patients:
Do not respond
Respond only partially
Experience adverse drug reactions (ADRs)
o Drug concentrations in plasma can vary more than 600-fold between 2 individuals (same
weight and same drug dosage)
• Factors that affect drug response variation:
o Physiological/pathological
Age
Renal excretion
Liver metabolism
Pregnancy
o Environmental
o Genetic factors:
find more resources at oneclass.com
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Ethnicity
Genetic differences can account for large amounts of variability
• Source of variation in DNA between individuals is due to SNPs (single nucleotide polymorphisms)
o Common in the population
o Most have no phenotypic effect
o May have an effect once a drug is added
o Not a mutation
o Would expect to see a normal distribution but if you see changes in concentrations ->
generally see in enzymes due to polymorphism
• Metabolism: once in how can a drug leave the body?
o Metabolism (biotransformation):
Liver microsomal enzymes
Makes lipid soluble drugs more water soluble so they can be excreted
Depends on different enzymes
Some are pro-drugs and are activated by metabolism
o Excretion:
Drugs are filtered by the kidney and excreted through urine, faeces, bile and
lungs
o Metabolism is biphasic:
Phase I
Phase II
o Does a lot, adds and breaks down -> changes
chemical structure
o Liver microsomal enzymes
o Oxidation/reduction/hydrolysis
-> produces a more water soluble metabolite
o Cytochrome p450 family
o Takes that change in chemical structure and
adds something to it i.e. bigger molecule to
make it more water soluble
o Liver microsomal or cytosolic enzymes
o Metabolite is combined with endogenous
molecule (eg. glucuronide acetyl)
-> produce even more water soluble
molecule
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• Cytochrome p450:
o Superfamily of microsomal (liver/small intestine) drug metabolising enzymes
o Main role is in the biosynthesis and degradation of endogenous substances (steroid
lipids and vitamins)
o Also has a role i etaolisig eoiotis
o Many different cytochromes have been identified
o 3 main families are associated with metabolism of drugs and are all polymorphic
-CYP1, CYP2, CYP3
• Consequences of polymorphism in CYP2D6:
No CYP2D6
-occurs in 20-30 million subjects
CYP2D6 gene duplications
-occurs in 15-20 million subjects
o Drug metabolism is too slow
o Drug levels too high at ordinary dose
o High risk for adverse effects
o No response from specific prodrugs (codeine
to morphine)
o Drug metabolism is too fast
o No drug response at ordinary dosage
(non-responders)
• Warfarin:
o Usually a long term drug
o Commonly prescribed
o High rate of adverse effects
o Maintenance doses are characterised by large inter-individual variability (range from 50-
fold)
o Metabolism occurs through CYP2c9
o Clinically relevant SNPs have been identified in CYPC29 (2 and 3)
-> results in reduced enzymatic activity and hence reduced metabolism
-> suffer from overdoses
o Warfarin also inhibits vitamin K epoxide reductase (VKROC1) affecting coagulation
proteins
o Additional variability is due to polymorphisms in vitamin K 2,3 VK0R1
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Pharmacogenetics, drug development from laboratory to clinic and case study agomelatine. Pharmacogenetics: pharmacogenetics: is the study of inter-individual variation in dna sequence related to pharmacokinetics or pharmacodynamics, target of a drug is a protein, protein is from a gene and genes are different in every individual. Inter-individual variability: for all major classes of drugs, a substantial proportion of patients: Experience adverse drug reactions (adrs: drug concentrations in plasma can vary more than 600-fold between 2 individuals (same weight and same drug dosage, factors that affect drug response variation, physiological/pathological. Makes lipid soluble drugs more water soluble so they can be excreted. Some are pro-drugs and are activated by metabolism: excretion: Drugs are filtered by the kidney and excreted through urine, faeces, bile and lungs: metabolism is biphasic: Phase i: does a lot, adds and breaks down -> changes chemical structure, liver microsomal enzymes, oxidation/reduction/hydrolysis. > produces a more water soluble metabolite: cytochrome p450 family.
