WEEK 2: Drugs and the liver Flashcards
Drugs administered per os are metabolized in the liver before they reach systemic circulation.
What is the process called?
Drugs administered per os are metabolized in the liver before they reach systemic circulation
(First pass metabolism)
▪ The liver is the primary site of drug metabolism.
▪ Biotransformation reactions are classically divided into Phase I and Phase 2 reactions
Define drug metabolism.
The metabolism of drugs can lead to the formation of various types of metabolites. Describe the different ways in which the metabolites can be formed.
Drug metabolism involves a series of reactions that alter the chemical structure of drugs, resulting in the formation of metabolites and to allow elimination from the body.
- Active drug →inactive drug
- Active drug → active or toxic metabolite
- Inactive prodrug → active drug
- Un-excretable drug → excretable drug
Define phase 1 reactions.
Phase I reactions involve the conversion of drugs into more polar metabolites by introducing or unmasking a functional group.
These reactions can include oxidation, reduction, hydrolysis, cyclization, decyclization, and addition or removal of oxygen or hydrogen
Phase I reactions are often catalyzed by enzymes called cytochrome P450 monooxygenases, which are primarily located in the endoplasmic reticulum of liver tissue
Name the 3 phase 1 reactions.
- Oxidation
- Reduction
- Hydrolysis
What happens in phase 1 reactions?
State the most common phase 1 reaction.
Name the enzymes that accounts for over 80%
of drug oxidation.
___________are a superfamily of enzymes
containing heme as a cofactor that function as
monooxygenases.
Introduce or unmask a polar functional group
▪ Oxidations are the most common reactions
▪ The cytochrome P-450 family accounts for over 80%
of drug oxidation.
▪ Cytochromes P450 are a superfamily of enzymes
containing heme as a cofactor that function as
monooxygenases
Describe CYTOCHROME P450-MEDIATED DRUG
OXIDATION.
- Activation: The drug molecule interacts with the active site of the cytochrome P450 enzyme, which is usually located in the endoplasmic reticulum of hepatocytes. This interaction positions the drug molecule for oxidation.
- Oxidation: Molecular oxygen (O2) is bound to the cytochrome P450 enzyme, and electrons are transferred from reduced nicotinamide adenine dinucleotide phosphate (NADPH) via cytochrome P450 reductase.
This electron transfer activates the oxygen molecule, leading to the formation of a highly reactive oxygen species known as a “cytochrome P450-iron-oxygen complex.”
Hydroxylation: The activated oxygen species attacks a susceptible site on the drug molecule, typically a carbon atom, resulting in the insertion of an oxygen atom.
This hydroxylation reaction introduces a hydroxyl (-OH) functional group into the drug molecule, rendering it more polar and facilitating its elimination from the body.
Product Formation: The oxidized drug molecule, now containing a hydroxyl group, undergoes further metabolism, such as conjugation with endogenous molecules like glucuronic acid or sulfate, to form water-soluble metabolites that can be excreted in urine or bile.
NOMENCLATURE: CYTOCHROME P450
ISOZYMES
State the 4 components that make up the nomenclature.
CYP3A4
Superfamily: CYP
Isoform family: 3
Isoform subfamily: A
Specific isozyme: 4
State the role of CP450 inducers and inhibitors.
CP450 inducers increase metabolism of substrates
* CP450 inhibitors decrease metabolism of substrates
State other non-CYP450 phase 1 reactions.
- Conversion of ethanol to acetaldehyde via alcohol dehydrogenase, in addition to
CYP2E1 - Biotransformation of catecholamines by monoamine oxidases
- Inactivation of 6-mercaptopurine by xanthine oxidase
Define phase 2 reactions.
Phase II reactions occur in the cytoplasm and involve the conjugation of drugs with endogenous hydrophilic groups, such as sulphates, glucuronides, glutathione, or amino acids.
This conjugation results in the formation of metabolites that are usually less toxic and more easily excreted.
Phase II reactions can further increase the polarity of drugs, facilitating their excretion.
State the 5 main phase 2 reactions.
- Glucuronidation
- Sulfation
- Acetylation
- Glutathione conjugation
- Methylation
What are conjugation reactions?
Which is the most common conjugation
reaction?
What type of metabolites are yeilded by phase 2 reactions?
▪ Phase 2 reactions also take place mainly in the liver.
▪ Conjugation reactions (Enzyme-catalyzed
combination of the drug with an endogenous
substance) form water-soluble compounds
▪ Glucuronidation is the most common conjugation
reaction
▪ Phase 2 reactions often yields inactive metabolites
▪ Note: Drugs already possessing –OH, -NH2 or –COOH
group may enter phase 2 directly and become
conjugated without prior phase 1 metabolism
What happens in glucuronidation?
Give examples of glucuronidation reactions involvement.
▪ Glucuronidation consists of transfer of the glucuronic acid to a substrate by UDP Glucoronyl-Transferases
▪ It is involved in metabolisms of bilirubin, steroid hormones, acetaminophen, chloramphenicol, morphine…
What is kernicterus?
Describe how it comes about.
Kernicterus is a rare but serious neurological condition that occurs as a result of severe jaundice in newborns.
Kernicterus occurs when unconjugated bilirubin, which is typically bound to albumin in the blood, crosses the blood-brain barrier and accumulates in the brain tissues.
This accumulation of bilirubin can lead to damage to the basal ganglia and other areas of the brain, resulting in neurological symptoms such as:
Muscle rigidity
Poor feeding
High-pitched crying
Lethargy
Arching of the back
Seizures
Developmental delays
Hearing loss
Intellectual disabilities
Movement disorders
- Neonates have inadequate expression of UDP glucoronyl transferases in their livers →Unconjugated hyperbilirubinemia→ Kernicterus .
Name the medication given to neonates with kernicterus.
Describe its MOA.
- Phenobarbital
Phenobarbital is a barbiturate medication primarily used as an anticonvulsant to treat seizures. It belongs to the class of drugs known as barbiturates, which act as central nervous system depressants. - Phenobarbital upregulates UDP glucoronyl transferase and can decrease the serum levels of unconjugated bilirubin.
