E1 L5: Hepatic Drug Metabolism Flashcards
Oxygen rich blood flows into the liver through the
Hepatic artery (20%)
blood flows out of the liver through
Hepatic veins
Nutrient rich blood coming from the bowel flows into the liver via
Portal vein (80%)
Bile composition
Water
Bile salts
Biirubin
Fats
Bile function
Surfactants
Helps fat digestion
Bilirubin elimination
Drug elimination
Portal triad
Hepatic vein, bile duct, and hepatic artery
Kupffer cell
Resident macrophage of the liver
Deal with bacteria
Bile flows from ____ and collects in the bile duct
Central vein
Lots of holes (fenestrae)
100-150nm (big holes)
Because of big holes - many molecules, including drugs, can leave the blood vessel and reach hepatocytes
Sinusoidal cells
Kupffer cell part of what system?
Reticuloendothelial system (RES)
Major cell of drug metabolism
Hepatocytes
70% of liver cells
Form Liver’s major metabolic and functional core (glucose metabolism, lipid metabolism)
Synthesis of plasma proteins such as albumin
Hepatocytes
Site where drug metabolizing enzymes are expressed and are responsible for drug metabolism
Hepatocyte
CYP450 - ER of hepatocyte
UGT - ER of hepatocyte
Principles of drug metabolism: Converts _____ chemicals into _____ which are readily excreted in urine or bile
Lipophilic -> hydrophilic
Certain compounds have ___ _____ effect, meaning they cannot be metabolized
First past
When a drug can be metabolized:
Chemical structure is modified
Goes under phase II reaction
eliminated into urine
Pumped into blood side
What two types of elimination makes up 90% of elimination
Hepatic metabolism and renal
(the rest are drugs that do not make it through eliminated in bile)
T/F: You do not always have to do phase I followed directly by phase II
True
-If chemical already has hydroxy, can go directly into phase II
4 major pathways of metabolism
Oxidation
UDP glucuronosyl transferase (UGT)
Hydrolysis
Reduction
What are the most common pathways of drug metabolism
Oxidation and conjugation
Hydrolysis mech
Ester group; add water, bond is cleaved and becomes carboxylic acid and alcohol
(Enzyme: Carboxyesterase)
Oxidation mech
Hydroxyl
Typically mediated by CYP450
Conjugation mech
Attach hydrophilic group to chemical
Usually mediated by UGT
Reduction mech
Undergoes reduction (keto group becomes alcohol)
Major enzyme: Carbonyl reductase
Where do metabolism pathways occur?
Liver
Two major enzyme classes in metabolism
CYP450 and UGT
Ranks 1st in catalytic versatility and the # of drugs it detoxifies among different enzymes
Highest level of drug metabolizing - is found in the liver (ER) among different tissues
Cyp450
Mono oxygenase
Less than 10 enzymes are responsible for drug metabolism
Reactions mediated by P450
Aromatic hydroxylation
Aliphatic hydroxylation
N-dealkylation
O-dealkylation
Cyp450 phenotyping
Add drug to different tubes - see which drug exhibits the best enzyme activity
Enzyme inducing drug:
Rifampin
Activates transcription factor PXR/ leading decreased exposure to enzyme substrates
Enzyme inhibiting drug
Ketoconazole
-Leads to increased substrate drug exposure
A collective term for microorganisms in human gut
Gut microbiota
The gut microbiota mediates certain drug metabolism, mainly -
Reduction and hydrolysis
Outnumber human cells by 3x
Involved in various biological functions, e.g. digestion of fiber
Gut microbiota
Double peak phenomenon is caused by
Enterohepatic cycling
Q: T/F: Kupffer cells are the primary cells in the liver responsible for drug metabolism
False - hepatocytes
Q: Choose two main (most common) drug metabolism reactions in the liver
Oxidation
Reduction
Hydrolysis
Conjugation
Oxidation - mediated by P450
conjugation - mediated by UGT
Q: T/F: Among CYP450 enzymes, CYP3A4 metabolizes the largest fraction of drugs
True
Q: T/F: The portal triad comprises the bile duct, portal vein, and central vein
False - bile duct, portal vein, hepatic artery
Q: T/F: Enzyme inducers of CYP3A4 would likely decrease the systemic exposure of CYP3A4 substrate
True (rifampin)
Q: T/F: Enzyme inhibitors of CYP3A4 would likely increase the systemic exposure of CYP3A4 substrate
True
