Flashcards in Pharmacokinetics: Metabolism & Elimination Deck (22):
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:
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?
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
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
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
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
Explain the stage of tubular secretion during renal excretion
Renal tubule has secretory transporters on both basolateral and apical membranes
These can transport basic or acidic compounds
This can result in a rapid decrease of Cp of unbound drug = rapid dissociation of any drugs bound to proteins in the plasma so it can be cleared from the body
Explain the stage of reabsorption during renal excretion
Body wants to retain some constituents of the glomerular filtrate
Uptake processes exist for carbohydrates, A.A's etc
Some drugs hijack these systems as substrates for the uptake processes
What is enterohepatic cycling?
The circulation of substances (e.g. bile salts) which are absorbed in the intestine, transported to the liver, secreted into the bile and again enter the intestine
How does enterohepatic cycling affect the concentration of a drug?
It regulates the Cp of certain drugs (those that conjugate with glucuronic acid) by stopping the body breaking it down with enzymes when the compound is actually required = maintains Cp
e.g. NSAIDs, morphine, oral contraceptives
Explain in detail how drugs become involved in the enterohepatic circulation
Drugs that conjugate the glucuronic acid enter the bile
These conjugates are too polar (ionised) so remain in the gut and are broken down by enzymes
This releases the parent molecule which is reabsorbed and processed by the liver again
It is therefore protected against excretion
List 2 factors that influence the rate of excretion
Blood flow - increased blood flow = increased excretion
Kinetics - ability of enzymes to become saturated, rate-limiting step, 1st order or 0 order for metabolism