Metabolism and Pharmacokinetics - more? Flashcards
What are some factors that affect Metabolism?
Age, genetic polymorphisms, route of administration, physiochemical properties of the drug
What are the phases of biotransformation?
Phase I - functionalisation, increase the reactivity with the addition of low-molecular-weight functional groups to expose or introduce a polar group
Phase II - conjugation, increase solubility with conjugation with a higher-molecular-weight water soluble group
What is the role of CYP450 in metabolism?
A microsomal enzyme responsible for the biotransformation of most drugs. They are a catalytically versatile family of enzymes that metabolise a large number of xenobiotics. Mostly found in the liver and gut, located in the phospholipid bilayer of smooth ER
They also play a vital role in biosynthesis or catabolism of endogenous molecules such as steroid hormones, bile acids, lipophilic vitamins, fatty acids and eicosanoids
NADPH-CYP oxidoreductase transfers electrons to CYP where it can oxidise xenobiotic substrates (in the presence of O2). Each CYP contains a molecule of iron-protoporphyrin IX that binds and activates O2
Explain Oxidation reactions in Phase I Biotransformation
Hydroxylation (addition of a OH group) occurs to oxidise aromatic compounds, or compounds containing heteroatoms
Explain Reduction reactions in Phase I Biotransformation
Aldehydes, ketones and nitro groups are reduced (addition of H2) using the reductase enzyme
Explain Hydrolysis reactions in Phase I Biotransformation
Esterase hydrolyses esters into acid and alcohol (ester + H2O > acid + alcohol).
Amidase hydrolyses amides into acid and amine
Explain Conjugation reactions in Phase II Biotransformation
Conjugation is catalysed by transferase enzymes. Glucuronic acid conjugation is the most common pathway
What is Xenobiotic Biotransformation?
Commonly converts lipophilic drugs into hydrophilic molecules. The liver and small intestine contain the highest concentration of xenobiotic biotransforming enzymes.
Can undergo different biotransformations:
- Active drug into inactive metabolite
- Active drug into active metabolite
- Inactive (pro)drug into active metabolite
- Active drug to toxic metabolite (biotoxification)
What are the Orders of Elimination?
- Zero order - a constant amount of drug is eliminated per unit of time independent of the drug concentration
- First order – a constant fraction of the drug is eliminated per unit time which is dependent upon the drug concentration
- Second order – elimination dependent upon the (drug concentration)^2
What are the Parameters of Pharmacokinetics?
- Cmax – maximum concentration after a single oral dose
- Tmax – the time at which Cmax occurs
- Kel – elimination rate constant
- T1/2 - half life
- AUC – area under the concentration-time curve
- F – absolute oral bioavailability
- V – volume of distribution
- CL – clearance
What is the equation for Exponential Decay?
C = C0 e-Kelt
Where C is the concentration after time t
How does CYP4 polymorphism effect metabolism?
Genetic polymorphisms and gene duplications are common in humans and can lead to increased or decreased enzyme activity. It can lead to issues in pharmaceutical industry such as therapeutic failure, adverse effects, toxicity and drug failure during development
Example of CYP polymorphism: Codeine is a prodrug metabolised in the liver into morphine (5-15%, most is converted into inactive metabolites) by CYP2D6. Most CYP2D6 alleles can produce either a non-functioning enzyme or an enzyme with decreased activity that can result in decreased pain relief. 1-2% of patients can carry multiple copies of CYP2D6 gene and can metabolize codeine more rapidly and completely, which may lead to morphine overdose or addiction
How are drugs excreted?
Excretion via the kidney - water soluble drugs/drug metabolites are efficiently eliminated, lipophilic drugs cannot be eliminated by kidneys efficiently. Lipophilic drugs must be metabolised to more polar products for excretion
Excretion via the hepatobiliary system - active excretion of drug molecules or their metabolites from hepatocytes into the bile and excreted in faeces
Excretion via the lungs or milk/sweat- negligible amounts excreted
