Pharmokinetics ( Metabolism + Elimination) Flashcards
Where does the majority of drug metabolism take place and with what enzymes ?
In the liver
- using phase 1 and phase 11 enzymes.
Phase 1 metabolism is carried out by …
Cytochrome P450 enzymes
Are CYP450s generalists or specific enzymes ?
Generalists - they metabolise a wide range of molecules
What sort of reactions to CYP450 catalyse ?
- dealkylation
- Redox reactions
- Hydroxylation reactions
- these enzymes INCREASE ionic charge of the drug molecule - now inactivating the drug - so it is eliminated directly or go onto phase 11 enzymes
Are all drugs deactivated after phase 1 metabolism?
No , some pro-drugs are in fact activated by phase 1 metabolism to active species
Give an example of a pro drug that is activated by CYP450 enzymes during phase 1 metabolism ?
- Codeine to Morphine
- this is a good thing , because morphine has 200 x greater affinity for opioid u receptors than codeine.
Phase 11 metabolism is carried out by …
Hepatic enzymes for example conjugating enzymes
Are phase 11 enzymes specific or generalists?
- they are still generalists but exhibit more rapid kinetics than phase 1 enzymes
What type of reactions do phase 11 enzymes catalyse ?
- sulphation
- glutathione conjugation
- methylation
- N-acetylation
- glucorinadation
- phase 11 enzymes metabolism drugs to further increase ionic charge
- phase 11 enzymes enhances renal elimination
How many superfamilies of cytochrome P450 are there ?
Three superfamilies : CYP 1 ,2 and 3
- izozyme members in each family coded by suffix : eg CYP(3)A4
What are a few factors that affect drug metabolism ?
AGE -
SEX - for example alcohol metabolism is slower in women
GENERAL HEALTH : hepatic / renal disease , CVS which results in decreased functional reserve
GENETIC FACTORS : genetic polymorphism , non expression of CYP450s
Other drugs can induce / inhibit CYP450s
Give an example of CYP450 induction
- CBZ ( carbamezepine) drug is an anti-epileptic drug that is metabolised by CYP3A4.
- CBZ induces CYP 3A4 - which lowers its own levels of CBZ affecting control of epilepsy. As rate of elimination will be increased and plasma levels of drug would then fall.
Give an example of CYP450 inhibition
- grapefruit juice inhibits CYP 3A4
- CYP 3A4 metabolises verapamil used to treat high blood pressure
- as a result of CYP3 A 4 being inhibited ( could be either competitive or non competitive ) blood pressure could be much reduced.
Give examples of how genetic variation can affect phase 1 metabolism
CYP2CP : not expressed in 1% Caucasians and 1%. Asian
- this enzyme metabolises NSAIDS, Tolubtamide , phenytoin
2) CYP2C19 : not expressed in 5% Caucasians and 30% Asians
- this enzyme metabolised omeprazole , Valium and phenytoin
Give an example of how genetic polymorphisms can effect drug metabolism,
- CYP2D6 gene is highly polymorphic
- CYP2D6 variants are categorised into : poor , normal/high , ultra rapid metabolisers
- Poor metabolisers : codeine to morphine - may not experience pain relief
- ultra rapid : codeine to morphine - may lead to morphine intoxication
Outline problems with the expression of CYP2D6 in different ethnic groups
- not expressed in 7% Caucasians
- hyperactive I’m 30% East Africans
- CYP2D6 metabolisers codeine into morphines and TCAS
What is the main route of drug elimination ?
Through the kidneys
What are other routes of drug elimination?
- bile
- lungs through vapour
- sweat
- tears
- genital secretions
- saliva
- breast milk
How are drugs eliminated out of the kidneys ?
1) first goes through glomerular filteration where the unbound drug then enters bowmans capsule
2) PCT : ionised drug molecules are carried out of the blood in the body into the kidney tubules from fenestrated capillaries into PCT cells via OATs and OCTs
3) DCT : passive reabsorption of lipid soluble , unionised drugs which have been concentrated at the lumen of the tubule because water is reabsorbed back into the blood. So these lipid soluble , unionised drugs move down their concentration gradient. Whereas the lipid insoluble , ionised drugs molecules move into urine
.
Define clearance
— the volume of plasma that is completely cleared of the drug per unit time
- CL is measured in ml/min or ml.min-1
- the volume is referred to Vd ( the apparent volume of distribution)
What is the clinical relevance of clearance and vD
- along with the concept of Vd , clearance predicts how long drug will stay in body
- is it clinically essential for : destining dosing schedule , therapeutic regime levels , minimising ADR
- together CL and Vd provide an estimate of drug half life
Define drug half life
The amount of time over which the concentration of a drug in plasma decreases to one half that initial concentration of drug
What is t1/2 dependant on and what is the formula
T1/2 is dependant on Vd and CL
t1/2 = 0.693 x Vd / CL
If CL stays the same and Vd increases , then T1/2 …..
Also increases
