Elimination Flashcards
What does clearance and exraction ratio represent?
Relates rate of elimination to [drug].
The apparent volume of plasma completely cleared of drug per unit time.
CLu is clearance of unbound drug
expressed as half life
halflife= (0.693*V) / CL
extraction ratio (ER) is the fraction of drug that is removed from the plasma as it crosses the eliminating organ (liver)
E=0 no elim E=1 complete elim
Clearance is the combination of the rate of excretion of the unchanged drug, as well as the rate of hepatic metabolism of the active drug
Liver physiology and sinusoids
Split into 4 main lobes, containing lobules, the basic functional unit of the liver.
contains the portal triad, containing a branch of the hepatic artery and the hepatic portal vein, a bile duct, lympatic vessels, and a branch of the vagus nerve.
the liver sinusoids are between hepatocyte plates and connect to the central vein. they are lined with sinusoidal endothelial cells and phagocytic kupffer cells.
factors that determine Hepatic elimination, and phases of metabolism reactions
Can only metabolise free, unbound drug.
Other tissue (e.g., GIT) also contain metabolic enzymes that play (a smaller) role in drug metabolism.
Phase 1 reactions (e.g., CYP) are hydrolysis, oxidation, reduction reactions
Phase 2 are conjugation reactions (e.g., glucuronidation, salvation, acetylation, methylation, glutathione, amino acid conjugations) to largely increase polarity of drug
Phase 1 reactions characteristics
CYP, flavin monooxygenase, esterases, amidases, hydrolyses, reductates, etc…
hydrolysis reactions break up larger molecules into two, e.g., carboxylesterases cleave at carboxyl bond, etc…
reduction reactions can reduce aldehydes, ketones, disulphides, sulfoxide, and quinone groups. can occur via direct chemical interactions with reducing compounds e.g., NADPH.
Oxidation reactions are most common. result in loss of an electron from drug. mainly CYP.
What parts of the drugs undergo CYP reactions (phase 1)
50 total enzymes (3A4 most abundant) 18 families of enzymes.
primarily catalyse mono-oxygenation reactions. Require O2 and NADPH for reaction. One of the oxygen atoms incorporated into substrate, other reduced to H20 by incorporating H from NADPH and the hydrogen that the oxidation reaction replaced from the substrate. e.g., C-H -> C-O
Alkyl and benzylic sites more likely to undergo the oxidation reactions.
Forms epoxides as intermediates in aromatic hydroxylation reactions. many are toxic.
What does Flavin monooxygenase (FMO) react with, and what co-factor needed
Xeno-substrate oxidising enzymes. FMO1-6 found in man. utilise FAD to oxidise its substrates. Located in the smooth ER.
Oxidises heteroatoms (S-, N-) to form oxides of these atoms. Also produces hydroxylamines of primary and secondary amines.v
UGT reactions (phase 2) and double peak phenomenon
21 isofroms. conjugates substrate with glucuronic acid to form O-, N-, S-, and C- glucuronides. these are water soluble and rapidly excreted in bile/kidneys. recognised by transporters.
Enterohepatic recirculation, which can result in the double peak phenomenon occurs when glucuronide conjugates (through biliary excretion) are metabolised by beta-glucuronidase in the gut to reproduce the original drug.
what are the targets of Sulfation (phase 2), and name of enzymes
conjugates a sulphate group to the substrate, metabolised by SULT enzymes. targets -OH and -NH2 groups. uses PAPS as a co-substrate
factors of the drug needed for Glutathionylation (phase 2) and characteristics of its metabolism.
GST enzymes metabolise it. conjugates glutathione (GSH) to C-, N-, and S- (electrophilic atoms).
often eliminated in the bile.
all substrates are hydrophobic, electrophobic, and react non-enzymatically with GSH too. very high conc of GSH in the liver
examples of enzymes that do Methylation and acetylation (phase 2)
Methylation is a common but minor pathway. e.g., COMT and POMT metabolise. major substrates are small endogenous compounds (e.g., NTs) and nucleic acids. decreases water solubility.
Acetylation uses co-substrate acetyl-CoA and conjugates a primary amine group (especially if aromatic). catalysed primarily by NAT1/2. makes it less water soluble.
what enzymes form Active metabolites and what are the benefits of prodrugs
Generally formed from phase 1 reactions, e.g., codeine -> morphine.
Prodrugs often have better oral bioavailability. Antibiotics are the biggest group of prodrugs, many are prodrugs of ampicillin.
mechanism of Reactive metabolites
Can each with DNA causing mutagenicity, carcinogenicity, or teratogenicity (malformation of embryo). can also react with proteins, causing organ toxicity, or immune hypersensitivity reactions.
Factors of the drug that determine biliary excretion, and transporters that aid in it
Occurs by active secretory transport (saturable). Drugs that have molecular weight above 300g/mol that also have both polar and lipophilic groups likely to be excreted in bile.
While most drugs have too low a molecular weight, conjugated metabolites can have molecular weight high enough for biliary excretion.
transporters that efflux drug into bile: ABCB11, ABCG2, ABCB1 (p-glycoprotein), ABCC2, and SLC47A.
Bile is taken up from the ileum to be recycled.
Factors affecting hepatic clearance
Hepatic blood flow, plasma protein binding (PPB), enzymatic and transporter activity. Disease state.
Hepatic blood flow affected by physical state e.g., resting vs exercising.
DDI and drug-food interactions as well as polymorphism affect enzyme and transporter activity.
Liver cirrhosis reduces clearance rate
Paracetamol metabolism by different enzymes and mechanism for NAPQI build up
At therapeutic doses: UGT (44-55%), SULT (20-30%), CYP followed by rapid GSH conjugation (15%)
CYP metabolism produces NAPQI, hepatotoxic. When GST becomes saturated, it builds up and covalently binds to protein and nucleic acids.
