Metabolism and Excretion Flashcards
Enterohepatic recirculation
Drugs that are eliminated in bile can be reabsorbed in GI tract
2 processes forming elimination?
Metabolism + excretion
Where does elimination mainly occur?
Kidney, liver, hepato-bilary system
Main purpose of metabolism?
make lipid soluble drugs more water soluble
Metabolism?
Enzymatic modification of a drug
Where does meatbolism occur?
Liver
Purpose of phase 1 metabolism?
Activate pro-drugs (introduce functional group)
What enzyme regulates phase 1 metabolism?
Cytochrome P450
Most common phase 1 metabolism?
Oxidation reaction
Result of phase 1 metabolism?
Decreased lipid solubility
Increase pharmacological activity (activate pro-drugs)
Where in liver/intestine is cytochrome P450 formed?
In ER or hepatocytes/enterocytes
What type of reaction is phase II metabolism?
Conjugation reaction
What part of the molecule does phase II metabolism target?
Functional group
End product of conjugation?
Further decreased lipid solubility and pharmacologically inactive molecule
Conjugation reaction?
Addition of group (acetyl, glucoronide) to decrease lipid solubility
Most common conjugate reaction phase II reaction?
Glucuronidation
Why are glucuronides inactive ad rapidly secreted?
Highly polar
What enzyme is used in glucoronidation?
UDP-glucoronyl transferase
How is paracetamol metabolised at therapeutic doses?
Mostly by phase II reaction by glucuronic acid
In liver
Minor proportion by cytochrome P450 = but this forms a toxic metabolite which is detoxified by phase II
How is paracetamol metabolised at overdose?
Phase II reaction substrates are saturated so more is metabolised by cytochrome P450 = more toxic metabolite
These react with liver proteins = tissue damage and hepatic necrosis
3 phases of renal excretion?
Glomerular filtration
Tubular secretion
Tubular reabsorption
How much fo drug is filtered at glomerulus?
20%
Rate of glomerular function dependent on?
Concentration of free drug in plasma and molecular weight
Why is albumin not filtered at glomerulus?
Molecular weight too high
Is glomerular filtration affected by lipid solubility or pH?
No
Where does active tubular secretion occur?
Proximal tubule
How is drug transferred into the lumen of proximal tubule?
Acids = acidic carrier against electrochemical gradient Bases = Organic carrier
Is PPB a barrier to carrier mediated transport?
No
How can competition occur in tubular secretion?
If drugs use same transporter
Where does tubular reabsorption occur?
Loop of Henle
As more water is reabsorbed how does drug concentration change?
Decreases
What is tubular reabsorption dependent on?
pKa lipid solubility
pH of tubular fluid
If tubule fluid is alkaline how will this affect reabsorption of acid and basic drugs?
Acids = ionised = won't pass through membrane = high urine concentration Bases = union ionised = pass through = less concentrated in urine
Impact of urinary acidification of excretion?
Acidic drugs = unionised so reabsorbed
Basic drugs = ionised = high concentration = more excretion
How do mechanisms of elimination depend on physicochemical properties?
a) lipid soluble
b) water soluble
c) volatile gases
a) metabolised to water soluble and excreted into urine
b) unchanged in urine
c) exhalation
Saturable elimination?
Above therapeutic dose the elimination mechanisms are saturated so not eliminated well
Clearance?
Volume of plasma cleared of compound per unit of time
How is clearance of IV calculated?
IV dose/AUC
How is clearance of oral dose calculated?
Oral dose X F/oral AUC
How can clearance be calculated without graph?
Ke x Vd
Ke
Elimination rate constant = slope of log concentration time
How is half life calculated?
0.693/Ke
Purpose of inducers?
Increase synthesis of phase I and II enzymes to increase metabolism
Implications of inducers?
Decrease drug effectiveness on chronic exposure
Need higher dose
Problem when withdrawn
How can alcohol consumption effect paracetamol metabolism?
Ethanol = induces cytochrome P450 = more metabolised by CYP450 = more toxic metabolite
