Drug Metabolism and Elimination Flashcards
What processes does elimination refer to?
This term refers to two processes
Metabolism:
Generally speaking, our body converts the drug molecules from a lipid-soluble version to a more water-soluble version and the water-soluble ones are more readily excreted by the kidneys
Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
Achieved by converting drugs into water-soluble molecules
So higher water-solubility enhances clearance of the drug
Mostly in the liver, but also in plasma, lung and intestinal epithelium
Excretion:
Removal of drug/metabolites from the body
Mostly in urine but also via bile/faeces, sweat, tears, saliva, exhaled air & milk
The last note is why some medications warn about taking the drug as a breastfeeding woman
The ones subject to excretion in milk tend to be more lipid-soluble drugs
What is clearance?
The volume of plasma cleared of drug per unit time
A constant clearance for drugs following 1st order kinetics
For a drug that is removed by liver metabolism and kidney excretion:
Plasma CL= hepatic CL+ renal CL
The value of a very high clearance wouldn’t be able to tell you how much of the drug has been metabolised in the liver or excreted in the kidney
Why is drug metabolism and excretion important?
Dosing issues:
Metabolism/clearance determine the amount of drug available at the site of action
Time taken for a drug to reach steady state levels
Safety issues:
Knowing what the drug metabolites are is very important
Metabolism may produce new chemical entities that may have their own effects
Components of racemic molecules (D/L) handled differently
Quite often only one of those isomers is pharmacologically active or being metabolised
Knowledge can aid design of future drugs
Drug metabolites measured in substance abuse test
How are drugs metabolised?
Drug removal begins immediately
Most undergo metabolism prior to removal- to increase excretion
Loss of (or reduced) biological activity because of increased polarity/less receptor binding
Some drugs are ‘activated’ by metabolism (known as prodrugs)
For example enalapril into active form enalaprilat by esterases present widely throughout the body
Enalapril is a cardiovascular prodrug
Some drugs eliminated unchanged skipping the metabolism process all together
Some metabolites are toxic
What happens during phase 1 of drug metabolism?
Drugs go through phase 1 reactions producing metabolites
These metabolites in turn get metabolised by phase 2 reactions
Phase 1 introduces chemically reactive groups
This is not activating the drug but rather making it more reactive
Main process is oxidation within the liver
Addition of oxygen molecules to carbon, nitrogen, sulphur molecules in drug structure
Carried out by cytochrome P450 enzymes (huge superfamily of enzymes mainly in liver)
They catalyse mostly oxidation but also reduction, sometimes at the same time
Bind drug + molecule oxygen
Oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
Types of phase 1 reactions: hydrolysis, hydration etc.
What happens during phase 2 of drug metabolism?
Phase 2 increases water solubility of drug for excretion
You find that quite bulky molecule side chains tends to be covalently bond to the phase 1 metabolites
Conjugates the Phase 1 product with an endogenous substance through production of stable covalent bonds
For example glucuronidation (reaction with glucose as the endogenous substances)
This increases water-solubility so that its not reabsorbed and excreted more easily
What is the exception to the drug metabolism rule?
Paracetamol metabolism
Rather than going in sequence; phase 1 then phase 2, its actually more readily metabolised by a phase 2 reaction, adding a whole glucose to the oxygen in the OH group which gives an inactive, safe, water-soluble metabolite that can be excreted
Similarly, a sulphate can be conjugated to paracetamol to give a water-soluble metabolite
If these enzymes are saturated, maybe from an overdose, then other processes will occur particularly a phase 1 type of reaction mediated by Cytochrome P450
This reaction produces quinone-imine as a metabolite which is very toxic as it covalently binds to proteins, which is permanent, so that it would impede their actions
Your body is able to cope with some level of it by conjugating a glutathione to make it water-soluble and non-toxic and be excreted.
The most cytochrome P450 is located in the liver which is why paracetamol is sometimes linked with liver damage
And this is much more relevant in cases of alcoholism
In alcoholism, it is thought that certain isoforms of Cytochrome P450 are upregulated, meaning they have increased expression and therefore more cytochrome P450 meaning that there’s more of the isoforms to turn paracetamol into the toxic quinone
If its upregulated to such an extent then it might start to overtake some of the phase 2 processes
How does excretion via the kidney occur?
Glomerulus filtration:
Filters <20kDa molecules
Amount excreted depends on the levels of drug bound to plasma proteins
Reabsorption:
As molecules pass through tubules they are concentrated, creating a large concentration gradient for reabsorption hence why we need to make drugs water-soluble.
Tubular excretion
Acid/base molecule carriers transporting molecules into tubular fluid transporting against the conc. gradient
Lower levels of unbound drug in plasma, pushing reaction for lower plasma proteins to release more free drug for secretion by carriers
The more tightly bound to the plasma protein then the less there is for filtration and secretion
Excretion= filtration - reabsorption + secretion
What is renal clearance?
The volume of plasma cleared of drug per unit time in one pass through the kidney
The drug is cleared from blood and appears in urine
For example the plasma [drug] is 10 ug/ml; drug is appearing in urine at 500ug/min, then its renal clearance is 50ml of plasma per min
Less renal elimination -> higher plasma half-life
Plasma CL= hepatic CL + renal CL
What factors affect drug metabolism and excretion?
These are just the four main ones
Age:
Cytochrome P450 activity reduced in neonates/elderly
Glomerular filtration rate (GFR) reduced greatly in neonates/elderly
Increased % fat content in elderly
Genetics:
E.g. 45% in Europe and USA; 80-90% Asians fast acetylators
E.g. 1/3000 slow metabolism by pseudocholinesterase
Drug metabolising enzymes:
Can be induced by other drugs or lifestyle factors such as smoking or a particular type of food etc.
Can be inhibited by other drugs or lifestyle factors “
Disease:
Liver disease impairs drug metabolism- drug toxicity
Renal disease may alter pharmacokinetics
And remember not all patients are the same
How does drug-drug interaction influence drug manufacturing?
In a clinical stage it has become routine to test for drug-drug interaction or sensitivity to particular enzymes (when these enzymes are well known to drug-drug interactions)
For example, a cardiovascular (anti hypotensive) likely to be used along side a statin would be designed where it wouldn’t interact with statins via the enzyme or any other pathways involved in the elimination process
Monitoring adverse effects is also important especially for drugs released in their first 1 or 2 years
Why monitor drug concentration?
For drugs that have a narrow therapeutic index
For drugs concentrations that relate well to either therapeutic effect or toxic effect or both
To individualise therapy
To confirm adherence of therapy
To diagnose toxicity
To determine the presence of drugs before starting therapy
As part of post-marketing surveillance to detect drug-drug interactions
