Drug disposition and PK Flashcards
Why should enteric coated tablets be taken on a fasted stomach?
Because if taken with a heavy meal where transit time can be delayed for up to 10 hours, the coating may degrade and therefore will no longer be effective
Why should poorly soluble drugs be taken with food?
Food will delay gastric emptying so there will be more time for dissolution of the drug, increasing the fraction of the drug that is reabsorbed
Why are poorly permeable drugs not good candidates for extended release formulations?
Because permeability varies along the wall of the GIT so if most of the drug doesn’t get released until it reaches the lower regions of GIT, where permeability is significantly lower, absorption will be hindered
Why does the extent of first pass metabolism vary along the regions of the GIT?
Because the expression of metabolic enzymes varies. Highest abundance being in the upper SI (duodenum), so based on where drug is released, extent of first pass will vary
What is the equation for bioavailability?
F = Fa x Fg x Fh
What are some of the implications of intestinal first pass metabolism?
Can result in low Fg as a result of extensive metabolism in enterocytes so will lead to a reduction in F
Transporter-metabolism interplay - additional factor leading to reduced F
Inhibition of intestinal enzymes and transporters -> DDIs
Which compound present in grapefruit juice causes an interaction with CYP enzymes?
Furanocoumarins
What is the interaction between grapefruit juice and CYP3A4?
Grapefruit juice irreversibly inhibits intestinal CYP3A4
Does grapefruit juice interact with hepatic CYP3A4?
A standard dose (i.e. glass of juice) does not affect hepatic CYP3A4
In the context of CYP3A4 and grapefruit juice, what is meant by irreversible inhibition?
Even if the inhibitor was removed, the enzyme would be inactive. The only way to recover the enzyme would be to produce a new protein
What happens if grapefruit juice is co-administered with a CYP3A4 substrate e.g. statin?
Metabolism and elimination of victim drug (i.e. statin) prevented so build up of victim drug and hence increased plasma levels -> toxicity
It is recommended that grapefruit juice isn’t consumed with all statins. True or false?
False - not all statins are metabolised by CYP3A4 so can be taken with statins that aren’t
What is the effect of grapefruit juice on Simvastatin in terms of AUC and Cmax
Increased Cmax and AUC -> increased risk of adverse effects e.g. myopathy
Name two statins that have low oral bioavailability due to extensive first pass met
Atorvastatin
Simvastatin
Name two drugs that are not statins that have low oral bioavailability due to extensive first pass met
Sildenafil
Verapamil
Why do drugs with extensive first pass metabolism show higher F when formulated as MR?
Because drug released in distal GIT, where fewer metabolic enzymes are present
What is the lowest Vd you can have and why?
3L - because that is the volume of plasma
What is the volume of total body water?
~40L
What is the volume of extracellular water?
~12L
Which PK parameter is important for determining the loading dose of a drug?
Volume of distribution
In general how does the volume of distribution of acidic drugs compare to that of basic drugs?
Vd of acidic drugs tends to be lower than that of basic drugs because acidic drugs tend to reside in plasma as they bind to plasma proteins. Vd of basic drugs is higher because they bind to acidic phospholipids in tissues, therefore leaving the blood/plasma and distributing
What is the volume of distribution of digoxin?
40L - similar to that of total body water
What does a low Vd indicate?
The drug may be highly protein bound and therefore doesn’t distribute well to tissues
What does a high Vd indicate?
Drug may be well distributed around the body OR may not distribute around the body only concentrates in certain tissue
When is a low Vd desirable?
When the drug target is vascular or extracellular
When is a high Vd desirable?
When the drug target is intracellular
At equilibrium, what determines the distribution of drug within the body?
Binding to plasma proteins and tissue components
Compare the lipophilicity of parent drugs and metabolites
Parent drugs are more lipophilic than metabolites. Metabolites reduce the lipophilicity of parent drug so that they are more polar and therefore more water-soluble so they can be eliminated by renal excretion
Renal clearance of metabolites is higher than than of parent drug. True or false?
True
Metabolites are less water soluble than parent drugs. True or false?
False
Name a pharmacologically active metabolite
ezetimibe glucuronide
What are the phase I drug metabolism reactions?
Oxidation
Reduction
Hydrolysis
What is the phase II metabolism reaction?
Conjugation
Which of the drug metabolism reactions is the most important?
Oxidation
Which group of enzymes catalyses oxidation metabolism reactions?
CYP450
What are the three different oxidation reactions in phase I metabolic reactions?
Aliphatic
Aromatic
De-alkylation
What are the two different mechanisms of oxidation reactions in phase I metabolic reactions?
Hydroxylation
Oxidative cleavage
What are the three reactions that take place during paracetamol metabolism?
N-hydroxylation
Glucuronidation
Sulfation
Excretion is only a function of the kidneys. True or false?
False - liver can also excrete drugs - biliary excretion
Pulmonary excretion can also take place
Which PK parameter primarily describes drug elimination?
Clearance
Would you expect two drugs with the same CL to have the same half-life?
Only if the two drugs have the same Vd as the 2 parameters that affect t1/2 are V and CL
What factors effect hepatic clearance of drugs?
Hepatic blood flow (affects drugs with high Eh)
Plasma binding (affects drugs with low Eh)
Enzyme activity
Transporter activity - uptake and efflux
Disease status
What can induce an increase in hepatic blood flow?
Bed rest
Thyrotoxicosis
Isoprenaline
What can induce a reduction in hepatic blood flow?
Exercise
Heart failure
Propranolol
What effect does liver cirrhosis have on hepatic clearance?
Reduced activity of metabolic enzymes
Changes in plasma protein binding as impaired albumin synthesis
hepatic clearance reduced
GFR impaired
What is the enterohepatic cycle?
Drug -> liver -> excreted in bile -> SI -> reabsorbed by portal vein -> liver
CYP3A4 is more specific to which drug it metabolises than CYP2C9. True or false?
False - CYP2C9 narrow specificity than 3A4
Ecstasy has a basic functional group. Which CYP enzyme is it most likely to be metabolised by?
CYP2D6
Tolbutamide has both lipophilic and hydrophilic groups. Which CYP enzyme is it most likely to be metabolised by?
CYP2C9
Midazolam is a bulky drug i.e. multiple rings in its structure. Which CYP enzyme is it most likely to be metabolised by?
CYP3A4
CYP3A4 only have the ability to metabolise drugs. True or false?
False - can metabolise endogenous compounds such as testosterone
Why is it important to know which drugs are metabolised by which CYPs?
Genetic polymorphism - some people lack gene for metabolisers and so drugs will build up
Polymorphism contributes to inter-patient variability
DDI potential
What is meant by the term ‘poor metaboliser’.
Lacks the gene for the CYP enzyme and so patient does not metabolise drugs that are substrates for that particular CYP enzyme
What are the therapeutic consequences of giving a drug that is a CYP2D6 substrate to a patient who is a poor metaboliser?
High plasma concentrations of drug as it is not metabolised and cleared -> toxicity
What is Ki?
the inhibitor-enzyme dissociation constant. It definees the affinity of an inhibitor to a particular enzyme
What does a low Ki value indicate?
A potent inhibitor for a particular enzyme
What are the two types of induction DDI?
Autoinduction and heteroinduction
What are the two major families of enzyme transporters in the human genome?
ATP-binding Cassette (ABC) - mainly efflux role Solute carrier (SLC) - uptake role
Where are the most relevant transporters expressed?
Epithelia of liver, kidney and intestines
Endothelium of BBB
Where are OATPs located?
Sinusoidal membrane of hepatocytes
What happens upon co-administration of OATP1B1 inhibitor with statins?
Increased plasma conc of statin as a result of reduced hepatocyte uptake -> increased risk of myopathy
