Drug Metabolism Flashcards
What is drug metabolism
A biochemical modification of pharmaceutical substances by living organisms usually through specialized enzymatic activity
Why is metabolism an essential pharmacokinetic process
It limits the life of a substance in the body, by rendering lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted
What happens to lipid soluble substances
They are passively reabsorbed from renal or extra renal excretory sites back into the blood
What are important sites in drug metabolism
Liver
Lining of gut
Kidneys
Lungs
What happens to most drugs before excretion
They are metabolised
What is the purpose of drug metabolism
To increase water solubility and so aid excretion
Or to deactivate compounds (which may involve a number of steps)
What happens to prodrugs following metabolism
They are activated
What happens to some drugs following metabolism
They form active metabolites
Give examples of prodrugs
Codeine
Enalapril
Simvastatin
Sacubitril
What are the effects of drug metabolism
The loss of pharmacological activity
A decrease in activity, with metabolites that show some activity
Increase in activity, more active metabolites (activation of a prodrug)
Production of toxic metabolites
What can the production of toxic metabolites in drug metabolism cause
Direct toxicity
Carcinogenesis
Teratogenesis
What can metabolising enzymes be divided into
Families and sub-families
What type of specificity do metabolising enzymes have
Wide substrate specificity
Individual drugs can be metabolised by more than one
Where is enzyme activity control regulated
At several levels
How are some enzymes expressed
Constitutively
Some are expressed or induced in the presence of a particular substrate
How many phases are there in enzyme metabolism
2
Phase 1
Phase 2
What occurs in phase 1
Oxidation, reduction and hydrolysis reactions
It increases the polarity of the compound and provides an active site for Phase 2 metabolism
What enzymes super family are important metabolising enzymes
Cytochrome P-450 enzymes
How is drug specificity determined
By the isoform of the cytochrome P-450
Specificity tends to be relative rather than absolute
What are the three most important families of the cytochrome P-450 superfamily that have been identified as important in oxidative drug metabolism
CYP1: isoform CYP1A2
CYP2: isoform CYP2D6
CYP3: isoform CYP3A4
What is the drug substrate for CYP1: isoform CYP1A2
Theophylline
What is the drug substrate for CYP2: isoform CYP2D6
Codeine
What is the drug substrate for CYP3: isoform CYP3A4
Cyclosporine
What is CYP3A4
The major constitutive enzyme in human liver and contributes to the metabolism of a wide range of drugs
Where can CYP3A4 be found
Liver
Gut
What is CYP3A4 also responsible for
The pre-sysytemic metabolism of several drugs
Give examples of drugs which use CYP3A4
Diazepam
Methadone
Simvastatin
CCBs
What is CYP2D6 responsible for
The metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine
What is found in 5-10% of the population in regards to CYP2D6
Reduced or absent expression so they may be immune to the analgesic actions of codeine
What is CYP1A2 induced by
Smoking so smokers will require a higher dose of theophylline than non smokers
What is CYP1A2 important in
Mmetabolism of theophylline
What does phase 2 metabolism involve
Conjugation
What does conjugation do
Increases the water solubility and enhance excretion of the metabolised compound
What does conjugation involve
The attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by Phase 1 metabolism
What does conjugation result in
Usually in inactivation however a small number of drug metabolites may be active
What factors affect metabolism (8)
Other drugs/herbals/natural substances Genetics Hepatic blood flow Liver disease Age Sex Ethnicity Pregnancy
How can drug metabolising enzymes be induced
From the increased metabolism of drugs metabolised by that enzyme which can result in decreased drug effects
What does the induction of an enzyme involve
Increased synthesis and therefore increased activity
What are common enzyme inducers
Alcohol
Smoking
Many drugs and herbals such as phenytoin and carbamazepine
What can commonly used drugs herbal medicines and food stuffs do
Inhibit drug metabolising enzymes which may be reversible or irreversible binding to the enzyme
What are common drugs or foods which can inhibit drug metabolising enzymes
Erythromycin, Clarithromycin
Grapefruit
How long does it take for the inhibition effect to occur
It is immediate
What can the wide variability in the response to drugs between individuals cause
Therapeutic failure or an adverse drug reaction
How many forms are Drug metabolising enzymes are often expressed in
Multiple
What does the multiple expression forms of drug metabolising enzymes cause
Inter-individual differences in gene expression (this is pharmacogenetics)
(Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme)
What will the lack or decreased activity of an enzyme usually result in
Increased drug toxicity
What can occur when there are multiple expressions of a particular metabolising enzyme
Enhanced metabolism and reduced drug effect or drug resistance.
State the 4 phenotype subpopulations of metabolizers
Poor metabolizers (PM) Intermediate metabolizers (IM) Extensive metabolizers (EM) Ultrarapid metabolizers (UM)
How can the variation in phenotype subpopulations of metabolizers occur
Due to racial background
What will poor metabolisers normally require
A smaller dose
What will ultrarapid meatbolisers normally require
An increased dose
What does CYP2C9 meatabolise
Name two of its substrates
16 commonly used drugs
Warfarin and phenytoin
How many allelic varients are known for CYP2C9
2
How many allelic varients are known for CYP2C19
8 which are all nonfunctional proteins
Which enzymes exhibit genetic variation (name at least 2)
Pseudocholinesterase N-Acetyltransferase (isoniazid is a substrate) Cytochrome P450 2D6 Cytochrome P450 2C19 TMPT -Thiomethylpurinetransferase Dihydropyrimidine Dehydrogenase
What type of enzymes does pseudocholinesterase
have
Typical and atypical enzymes
What type of enzymes does N-Acetyltransferase (isoniazid is a substrate) have
Fast acetylation
Slow acetylation
What happens to drug metabolising enzymes in foetuses and premature infants
They are either deficient or reduced (normally)
What else can be deficient in foetuses and premature infants
Renal function so drug and metabolites rapidly build up to toxic levels
How well can children metabolise drugs by the age of 2
More rapidly than adults
What is the rate of metabolism by puberty
Greater than that of adults
In what pharmacokinetic areas have sex-based differences been found
Absorption, Distribution, Metabolism, and Elimination
What is induced in pregnancy
The induction of certain drug metabolizing enzymes occurs in second and third trimester
What can have a profound effect on drug metabolism
Hormonal changes during development
What parameters in the elderly can affect drug metabolism
Plasma protein, lean body mass and liver weight which decrease significantly
Also chronic disease is also more common so they are likely to be on multiple drug therapy
How can race affect drug metabolism
There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms
Why is ADME important
To determine how to get the drug to its site of action
To determine dose and frequency
Making sure the drug is present in an effective dose
Predicting and avoiding toxicity
Making changes based on other drugs, illness or physiological factors
