l9 pharm

what is the main focus of Metabolism II?

Metabolism II focuses on Phase II metabolism, where the body attaches polar groups to drugs so they become easier to eliminate

what is the main purpose of Phase II metabolism?

to make drugs more water-soluble so they can be eliminated more easily from the body

what is the general pathway from drug to excretion?

drug → Phase I metabolism → Phase II conjugation → excretion

what does Phase II metabolism attach to drugs?

Phase II metabolism attaches polar endogenous molecules/groups to drugs

what does conjugation mean in Phase II metabolism?

conjugation means attaching another molecule/group onto a drug to make it more water-soluble

how does Phase II metabolism differ from Phase I metabolism?

Phase I usually modifies the drug with small chemical changes, while Phase II attaches a larger polar group to the drug

what is the simple difference between Phase I and Phase II?

Phase I = modify the drug. Phase II = attach something onto the drug

what are the main Phase I reactions?

oxidation, reduction, and hydrolysis

what are the main Phase II reactions from this lecture?

glucuronidation, sulphation, and glutathione conjugation

what does Phase II metabolism do to molecular weight?

it increases molecular weight because another group/molecule is added to the drug

what does Phase II metabolism do to polarity?

it increases polarity, making the drug more water-soluble

why does increased polarity help drug elimination?

polar drugs are more water-soluble, so they are easier to excrete in urine or bile

what does “Drug → conjugate → kidney/bile” mean?

the drug is conjugated in Phase II, then the conjugate can be excreted through the kidney or bile

what does endogenous mean?

endogenous means something comes from inside the body

what endogenous molecules are used in Phase II metabolism?

glucuronic acid, sulphate, and glutathione

what is a conjugate?

a conjugate is the product formed when a drug has another molecule/group attached to it

what are the three main enzyme systems for Phase II metabolism?

UGT enzymes, sulfotransferases, and glutathione-S-transferases

what do UGT enzymes do?

UGT enzymes catalyse glucuronidation, attaching glucuronic acid to drugs

what does UGT stand for?

UDP-glucuronosyltransferase

what do sulfotransferases do?

sulfotransferases catalyse sulphation, attaching sulphate groups to drugs

what does ST stand for?

sulfotransferase

what do glutathione-S-transferases do?

glutathione-S-transferases catalyse glutathione conjugation, helping detoxify reactive metabolites

what does GST stand for?

glutathione-S-transferase

what is the general Phase II reaction?

drug + conjugate → conjugated drug

what are functional groups?

functional groups are reactive chemical groups on a molecule, such as OH, NH₂, or carboxyl groups

why are functional groups important for Phase II metabolism?

Phase II enzymes often attach conjugates onto functional groups created or exposed by Phase I metabolism

what functional groups can Phase I introduce?

hydroxyl groups, amines, and carboxyl groups

what does Drug-OH → Drug-O-glucuronide mean?

a drug with an OH group has glucuronic acid attached to it, forming a glucuronide conjugate

why does Phase II often depend on Phase I?

Phase I can create the functional group that Phase II needs in order to attach the conjugate

what are cofactors in Phase II metabolism?

cofactors are molecules that provide the conjugate group needed for the Phase II reaction

why do Phase II reactions require high-energy cofactors?

because the conjugate groups must be activated before they can be attached to drugs

what cofactor is used for glucuronidation?

UDP-glucuronic acid

what cofactor is used for sulphation?

PAPS

what cofactor/conjugate is used for glutathione conjugation?

glutathione

why does ATP matter for Phase II metabolism?

ATP is needed to synthesise the high-energy cofactors used in Phase II reactions

what is the most important Phase II reaction in humans?

glucuronidation

where does most glucuronidation occur?

mainly in the liver

what enzyme catalyses glucuronidation?

UDP-glucuronosyltransferase, or UGT

what does glucuronidation add to drugs?

glucuronic acid

what is the effect of adding glucuronic acid to a drug?

it makes the drug a large polar conjugate that is highly water-soluble

what are the outcomes of glucuronidation?

easier renal excretion and easier biliary excretion

what does renal excretion mean?

excretion through the kidney into urine

what does biliary excretion mean?

excretion through bile into the intestine

why can’t free glucuronic acid react directly?

it needs to be activated first before UGT enzymes can attach it to drugs

what is UDPGA?

UDPGA is uridine diphosphate glucuronic acid, the activated form of glucuronic acid

what is UDPGA used for?

UDPGA is the substrate used by UGT enzymes for glucuronidation

what is an example of an anticancer drug metabolised by glucuronidation?

irinotecan

what is the clinical point of glucuronidation of many anticancer drugs?

glucuronidation often inactivates drugs

does glucuronidation usually activate or inactivate drugs?

it often inactivates drugs

what is enterohepatic recycling?

enterohepatic recycling is when a drug cycles between liver, bile, intestine, and reabsorption back into the body

what is the first step of enterohepatic recycling?

a drug glucuronide is secreted into bile

what enzyme do intestinal bacteria produce that affects glucuronides?

beta-glucuronidase

what does beta-glucuronidase do?

it breaks/hydrolyses glucuronide conjugates, removing glucuronic acid

what happens after a glucuronide conjugate is hydrolysed in the intestine?

the unconjugated drug can be reabsorbed

why does enterohepatic recycling prolong drug action?

because the drug is reabsorbed and gets another cycle through the body

what does enterohepatic recycling do to half-life?

it prolongs drug half-life

what does half-life mean?

half-life is the time taken for the drug concentration to fall by half

what is glutathione conjugation mainly used for?

it protects cells by detoxifying reactive toxic metabolites

what enzyme catalyses glutathione conjugation?

glutathione-S-transferase, or GST

what molecule is attached in glutathione conjugation?

glutathione

what does glutathione detoxify?

reactive electrophiles and toxic metabolites

what are reactive electrophiles?

reactive molecules that can damage cell components such as proteins, DNA, or membranes

why is glutathione protective?

it binds to reactive toxic metabolites and makes them less harmful

how is glutathione involved in paracetamol toxicity?

glutathione normally detoxifies the toxic paracetamol metabolite, but in overdose glutathione can run out

what happens in normal paracetamol metabolism with glutathione?

the toxic metabolite is detoxified by glutathione

what happens in paracetamol overdose?

glutathione is depleted and the toxic metabolite accumulates

what does glutathione depletion mean?

glutathione depletion means glutathione stores are used up

why is glutathione depletion dangerous?

toxic metabolites can accumulate and damage cells, especially liver cells

what is the toxic metabolite of paracetamol?

NAPQI

what happens when NAPQI accumulates?

it can cause liver damage

what is the major treatment for paracetamol overdose?

N-acetylcysteine

what does N-acetylcysteine do?

it supplies cysteine, which helps restore glutathione

what is cysteine?

cysteine is a precursor used to make glutathione

why does N-acetylcysteine help in paracetamol poisoning?

it helps the body make more glutathione, which detoxifies the toxic metabolite

what is sulphation?

sulphation is a Phase II conjugation reaction where a sulphate group is attached to a drug

what enzyme catalyses sulphation?

sulfotransferases, or ST

what kinds of groups are targets for sulphation?

phenols, alcohols, and amines

what cofactor is needed for sulphation?

PAPS

what does PAPS stand for?

3’-phosphoadenosine-5’-phosphosulfate

what does PAPS provide?

PAPS provides the sulphate group for sulphation

why does sulphation capacity depend on PAPS availability?

because if PAPS is limited, sulphate groups cannot be transferred efficiently

which Phase II enzymes are high-capacity?

UGT enzymes are high-capacity

which Phase II enzymes are low-capacity?

sulfotransferases are low-capacity

what does it mean if an enzyme pathway saturates quickly?

it reaches its maximum metabolic rate quickly, so extra drug cannot be metabolised through that pathway as easily

why is enzyme capacity important in drug metabolism?

because low-capacity pathways can become saturated, changing how much drug or toxic metabolite builds up

what nutrients are important for Phase II cofactor synthesis?

niacin, cysteine, and sulphate

what does niacin help produce?

NADPH

what is cysteine needed for?

glutathione synthesis

what is sulphate needed for?

PAPS synthesis

how can low cysteine affect drug metabolism?

low cysteine can reduce glutathione synthesis

how can low sulphate affect drug metabolism?

low sulphate can reduce sulphation

what is the clinical implication of nutritional deficiencies?

diet and nutrient status can affect drug metabolism

why does diet affect drug metabolism?

because nutrients are needed to make cofactors used in Phase II metabolism

how do species differ in Phase II metabolism?

different species have different capacities for Phase II pathways such as glucuronidation

which species have strong glucuronidation capacity?

humans and pigs

which species has poor glucuronidation capacity?

cats

why are cats sensitive to paracetamol toxicity?

cats have low glucuronidation capacity, so toxic metabolites can accumulate

what happens when cats are given paracetamol?

poor glucuronidation can lead to toxic metabolite accumulation and serious toxicity

what is the key species example from this lecture?

cats have poor glucuronidation and are highly sensitive to paracetamol toxicity

what is Δ9-THC?

Δ9-THC is the main psychoactive compound in cannabis, used here as an example of Phase I and Phase II metabolism