Pharmacokinetics: Metabolism & Elimination Flashcards
Where does metabolism occur?
Tissue level = liver, kidney (filter), lungs
Intracellular level = mitochondria, smooth ER
Why does the body metabolise the parent compound in the metabolite?
Trying to convert parent compound into something that’s more amenable to excretion (urine) = more polar = more water-soluble
= reduction in biological activity
However metabolism can sometimes increase biological activity as well
Describe the stages of metabolism
Phase I Phase II Drug ------> Metabolite ------> Conjugate Drug = parent compound Metabolite = derivative Conjugate = add ons
What occurs during Phase I of metabolism?
Preparing drug for conjugation (e.g. opening up functional groups)
3 main reaction occur to change the drug’s structure:
Oxidation
Reduction
Hydrolysis
What is the role of Cytochrome P450 in Phase I metabolism?
Isoenzymes, found in smooth ER
Variety within family to metabolise a variety of compounds in order to prepare them for conjugation
Explain how cytochrome P450 prepares a compound for conjugation
Drug molecule interacts with cytochrome P450 enzyme
It becomes oxidised (remove electrons)
Compound (metabolite) is now ready for conjugation
What occurs during Phase II metabolism?
Reactions which involve the formation of covalent bonds
This results in a water-soluble conjugate = can be excreted in urine more easily
Products of Phase II are often inactive, however in some cases activity is retained
e.g. codeine –> morphine = increased analgesic effects
When does first pass metabolism occur?
Metabolism begins before the drug reaches the general circulation
Which sites in the body are involved in first pass metabolism?
Liver
Lung
Intestinal lumen
Intestinal wall
List 2 factors which influence metabolism
Genetic influences e.g. enzymes, genes
External factors e.g. grapefruit (increases Cp as it inhibits CYP3A4 enzyme)
List 3 types of drug which should not be combined with grapefruit juice
Statins
Immunosuppressants
Calcium channel blockers
Explain the 4 types of metabolisers
Poor metabolisers = inherited a non-functional gene from each parents = no CYP2D6 activity
Intermediate metabolisers = inherited 1 non-functional gene = some CYP2D6 activity
Ultra rapid metabolisers = higher than normal CYP2D6 activity
Extensive metabolisers = most people have at least 1 functional gene = normal CYP2D6
List 3 routes of excretion
In:
Fluids = urine, bile, sweat (important for low MW compounds)
Solids = faeces, hair (important for high MW compounds, some drugs passing straight the body)
Gases = expired air (important for volatile compounds, e.g. ethanol for breathalyser)
List the 3 main stages of renal excretion
Glomerular filtration
Tubular secretion
Reabsorption
Explain the stage of glomerular filtration during renal excretion
Occurs under hydrostatic pressure
Pores allow passage of small molecules (below 20 kDa)
Filtrate contains about 20% of the plasma volume delivered
Molecules = small, low MW, water soluble, unbound