Pharmacokinetics 3 (Elimination) Flashcards
drug needs to be _____ polar to be excreted out successfully
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GI tract draining all of absorbing material into
liver
What is the advantage of GI tract draining all of absorbing material into liver
breaks bigger molecule into smaller molecules. then if molecules needs to go back into GI tract (e.g. if still too big).
hepatic artery > liver >
hepatic vein
s the name of the process when molecules goes back and fourth from GI to liver
hendro-hepatic recirculation
Mesenteric artery > liver >
hepatic portal vein
what is the most common site of action for drug metabolism
liver
can lipophilic drug be polar?
no
later on drug will be introduced in liver to make drug MORE
soluble and able to travel through liver
gut > liver (> kidney) >
site of action
Which enzymes facilitate the chemical process to make drugs more water soluble?
DMEs
Cytochrome P450
Alcohol dehydrogenase (ethanol)
Esterases
What are the two step process of drug metabolism?
Phase I = oxidation, reduction, hydrolysis
Phase II = conjugation
Phase 1 is catalysed by Cytochrome P450 (Haem-containing mono-oxygenase enzymes)
74 CYP gene families and multiple substrates
CYPs evolved to deal with environmental/nutritional toxins (e.g. plant alkaloids)
Some drugs or foods can increase the expression of specific CYPs (phenytoin, broccoli)
Some drugs or foods can inhibit the CYPs activity (grape fruit juice)
Metabolites could be more active than the drug (pro drugs)
What does phase 1 require?
oxygen and NADPH
Phase II is conjugation=
ADDITION of polar groups
(convert drugs more water soluble, that could most readily excreted by kidney)
examples of polar groups that can be added to drugs
OH (glucuronyl, methyl, sulphate)
NH2 (glucuronyl, acetyl)
COOH (glucuronyl, glycine)
the most common phase II catalysis is by…
Uridine-disphospho-glucuronyl transferases (UGTs)
Drug Excretion/Elimination
Water soluble molecules:
Urinary system (Kidneys)- Major site of drug eliminations (3 stages)
passive or not passive = glomerular filtration?
removal of [free] drugs
Tubular secretion = what kind of transport?
active transport
Reabsorption depends on _____ _______ & ___
lipid solubility & pH
Biliary system (entero-hepatic recirculation)
Large molecule
Describe the process of Drug Excretion/Elimination?
Active transport of large molecule into bile (glucuronides)
Excreted into gut
Redistribution of molecules into liver
Reabsorption can be blocked by activated charcoal (e.g. treatment method for drug poisoning)
Drug in blood continually changes with time because of
ADME
drug {dose} intravenous >
kelimination (Kel)
higher absorbed drug
eliminated at a higher rate
intravenously = advantage
drug is available in plasma immediately - 100% absorbed
How to find out elimination rate?
[Drug]t = [Drug]0 e^-k el t
Elimination measures (Half-life)
Half-life (t1/2) = time taken to reduce the plasma drug concentration by half from the administered [drug] or a time at which 50% of drug eliminated from plasma
Half-life is calculated from the exponential curve (linear plot)
Slope of the log (best linear fit) = Kel
Half-life is calculated from the exponential curve (linear plot)
Slope of the log (best linear fit) = Kel
Elimination measures (Plasma clearance, CLp)
CLp is the volume of plasma (ml) that is cleared of drug in unit of time (min): e.g. xy ml/min
CLp = CLliver + CLrenal
Interrelationships of measures (Vd, Kel, CLp and t1/2)
kel = CLp / Vd
t1/2 = 0.693 / kel = 0.693d / CL p
Summary of drug excretion/ Elimination:
Drugs are metabolised to more water soluble
Phase I process is catalysed by CytochromeP450 and Phase II process is by UDP glucuronyl transferases
The water soluble drug metabolites are excreted via kidneys and large molecules are processed through biliary (entero-hepatic recirculation process).
Renal excretion depends on filtration and active transport
Lipid solubility modulate the kinetics of drug reabsorption
Drug elimination (most) follow first order kinetics.
Half-life and plasma clearance rate are commonly used to determine drug elimination kinetics
Volume of distribution, plasma clearance and half-life are interrelated
BNF pharmacokinetics profile
if lipophilic drug is higher, distribution?
curve on graph tells you the
RATE of elimination
