Drug Metabolism and Elimination
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Why do we need metabolism of drugs?
In order for removal of lipid-soluble drug molecules to prevent reabsorption by kidneys. Achieved by converting drugs into water-soluble molecules.
Where does metabolism occur?
Mostly in the liver, but also in the plasma, lung and intestinal epithelium.
What is excretion?
The removal of drug or metabolites (of drug) from the body. Mostly in urine, but also via bile/faeces, sweat, tears, saiva, exhaled air + milk.
What are dosing issues with drug metabolism and excretion?
Metabolism / clearance determine the amount of drug available at site of action and the time taken for a drug to reach steady state levels.
What are safety issues with drug metabolism and excretion?
Metabolism produces new chemical entities that may have their own effects (eg. toxcitiy). Components of racemic molecules (D/L) handled differently.
When does drug removal begin in the body?
Immediately
Do most drugs undergo metabolism first or go straight to excretion?
Most undergo metabolism prior to removal - this helps to increase excretion (of the metabolites)
Following metabolism, why can some drugs no longer act at their therepautic targets?
Due to loss (or reduction) of biological activity - the polarity has been increased, which reduces receptor binding.
What is a prodrug?
These are the drugs that are activated by metabolism - so rely on the metabolism process to be able to act at their therepeautic targets. Eg. Enalapril (ACE inhibitor) into active form enalaprilat by esterases.
Some drugs eliminated remain unchanged. Example?
Eg. Digoxin - remains unchanged, not metabolised. Eliminated as digoxin.
What are the two phases of drug metabolism?
• Phase 1 - introduces chemically reactive groups • Phase 2 - increases water solubility of drug for excretion
Describe phase 1 reaction of drug metabolism
• Introducing chemically reactive groups • Main process oxidation (others: hydrolysis, hydration) • Addition of oxygen molecules to C, N, S molecules in drug structure • Carried out by cytochrome P450 enzymes (huge superfamily of enzymes in liver), they: • > bind drug + oxygen molecule • > oxidation of drug occurs through 1 O atom, the other O atom is reduced to H2O.
Phase 1 has produced a reactive metabolite (or active drug). Now describe phase 2 reaction of drug metabolism
• Now to increase water slubility of drug for excretion • Conjugates phase 1 product with an enodgenous substance through production of stable covalent bonds • Eg. glucuronidation (rxn w/ glucose) • Results in water soluble metabolite
How is the metabolism of paracetamol an exception to the phase 1 and 2 rule?
• Phase 2 before phase 1 • Prefers to use phase 2 via conjugation w/ glucose + sulphate • Produces non-toxic, water soluble products • Phase 1 metabolism only significant when glucuronidation + sulphate conj saturated. So in overdose, when the phase 2 pathway is saturated, phase 1 is used -> produces TOXIC intermediate.
What are 3 important stages of exretion via the kidney?
• Glomerulus filtration - amount excreted depends on levels of drug bound to plasma proteins • Reabsorption - need to be water-soluble to prevent this • Tubular secretion - more free drug for secretion by carriers Excretion = filtration - reabsorption + secretion
What is renal clearance?
• Volume of plasma cleared of drug per unit time in one pass through the kidney • Drug is cleared from blood + appears in urine • renal clearance = [drug] urine / [drug] plasma • Reduced renal elimination indicates an increased plasma half life
How does age affect drug metabolism and excretion?
• Cytochrome P450 activity reduced in neonates/elderly • GFR reduced greatly in neonates/elderly • Increased % fat content in elderly Genetics also impact.
How do liver and renal disease impact on drug metabolism and excretion?
Liver disease impairs drug metabolism leading to drug toxcitiy and renal disease may alter pharmacokinetics.
Why does drug concentration need to be monitored?
• For drugs that have narrow therepeautic index • To individualise therapy • To confirm adherence of therapy • To diagnose toxicity • To determine presence of other drugs before therapy • Part of post-marketing surveillance to detect drug-drug interactions