Drug Metabolism and Elimination Flashcards
In terms of elimination, what are drug metabolism and excretion?
- Metabolism
Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
Achieved by converting drugs into water-soluble molecules
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
Both are involved in ELIMINATION
What is drug 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 CLEARANCE - the volume of plasma cleared of drug per unit of time
* Plasma clearance = Renal artery clearance + Hepatic clearance
RENAL CLEARANCE is the volume of plasma cleared of drug per unit of time through one pass of the kidney
Why is studying metabolism and excretion important?
- Dosing issues
Metabolism / clearance determine the amount of drug available at site of action through the amount of drug supplied removed from body,and time taken for a drug to reach steady state levels - Safety issues
Metabolism produces new chemical entities that may have their own effects
Components of racemic molecules (D/L) handled differently – the concentration of a D form drug can sometimes be double the concentration of an L form drug.
Give further details about drug metabolism
- Drug removal/metabolism begins immediately
- Most undergo metabolism prior to excretion
- Some drugs are “activated” by metabolism (prodrug) e.g. enalapril into active form enalaprilat by esterases
There are 2 phases of metabolism.
Describe phase 1 of drug metabolism
Phase 1 introduces chemically reactive groups
* 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 in liver) which bind the drug and oxygen molecule
* Oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
Describe phase 2 drug metabolism
- Phase 2 increases water solubility of drug for excretion
- Conjugates the Phase 1 product with an endogenous substance through production of stable covalent bonds
e.g. glucuronidation (reaction with glucose) and sulfate conjugation
How is paracetamol metabolised
The metabolism of paracetamol is an exception to the 2-phase rule.
- It does not need phase 1 reaction, it can be readily metabolised using phase 2 reactions, by adding a sulphate or glucuronide group, , instead of a hydroxyl, and this converts the paracetamol into two water-soluble, benign conjugates that will be excreted readily by the kidney.
Describe glomerular filtration and when it is used
- Glomerulus filtration
Filters <20kDa molecules
Amount excreted depends on levels of drug bound to plasma proteins
Occurs with unbound drugs
Describe 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
- E.g. the plasma [drug] is 10 µg/ml; drug is appearing in urine at 500 µg/min, then its renal clearance is 50 ml/min
- ↓ renal elimination = ↑ plasma half-life
What factors affect drug metabolism?
-age: cytochrome p450 activity decreases in the elderly and neonates.
-genetics: 45% of europeans, 80-90% of asians have fast acetylators which increase metabolism.
-drug metabolising enzymes: induced(metabolised more rapidly) /inhibited (metabolised more slowly ) by other drugs and lifestyle factors
-disease: liver and renal disease impairs metabolism
Why are drug concentrations monitored?
-to individualise therapy
-to confirm adherence of therapy
-to diagnose toxicity
-to determine presence of other drugs before starting therapy
Give further examples of drug excretion outside of the kidneys.
- Excretion of drugs in breast milk → unwanted effects in the nursing infant
- Excretion from lungs: e.g. anaesthetic gases
- Excretion of drugs into sweat, saliva, and tears: quantitatively
unimportant
Excretion by these routes depends mainly on diffusion of the unionised
lipid soluble form of drugs through the epithelial cells and depends on pH
Why is paracetamol saturation dangerous?
If too much paracetamol, glucuronidation and sulphate conjugation would be saturated, meaning that it would go through phase 1 first. The cytochrome P450 then creates a toxic quinone-imine intermediate. This toxic substance is very reactive and will bind to body’s proteins, changing their shape, thus altering their effectivity.
When is tubular reabsorption used and why is it needed
As molecules pass through tubules they become concentrated, creating large concentration gradient for reabsorption – hence need to make drugs water-soluble. Some drugs (e.g. lipophilic drugs) are passively reabsorbed by the kidneys while there is also active reabsorption of acidic and basic endogenous compounds. Reabsorption of drugs depends on urine pH and pKa of the drug.
When is tubular secretion used?
