Lecture 3 - metabolism of drugs Flashcards
what is biotransformation?
major mechanism for drug elimination
What is the product after the compund is broken down and what are their normal characteristics?
they are now called metabolites
more polar
What happens when the metabolites are pharmacologically inert?
metabolism inactivates the effect on the body
what are xenobiotics?
compounds that the organism cannot use as foods, and harmfull if they accumulate - no metabolic effect
what are some examples of xenobiotics?
synthetic drugs
natural poisons
antibiotics
how are xenobiotics detoxified?
by a set of xenobiotic-metabolizing enzymes
what are some examples of xenobiotic metabolizing enzymes?
cytochrome P450 oxidases
UDP-glucoronosyl transferases
glutathione S-transferase
how does the xenobiotic-metabolizing enzymes function?
they act in two stages
- oxidizes the xenobiotic
- conjugate water-soluable groups onto the molecule
where is the majority of small-molecule drug metabolism carried out? and by what enzymes?
- liver
- cytochrome p450 enzymes -redox
what are some possible consequences of biotransformation?
production of inactive metabolites w/
- increased or decreased potencies
- qualitatively different pharmacologic actions
- toxic metabolites
- active metabolites from inactive prodrugs
What is a prodrug?
when the metabolites are more active than the parent drug
What does the increase inpolarity mean for the metabolites?
they have a more rapid rate of clearance because of possible secretion by acids or base carriers in the kidney
tubular reabsorption
Which organ is the major site of biotransformation?
liver
What may effect the biotransformation of the drug?
prior administration of that drug
diet
hormonal status
genetics
diseases
age
developmental status
liver function
How can we classify biotransformational reactions?
Phase I - nonsynthetic reactions
Phase II - synthetic reactions
What happens during phase I in biotransformation reactions?
it involves enzyme-catalyzed biotransformations of the drug without any conjugations
what reactions may occur in phase I
oxidations
reductions
hydrolysis reactions - frequently introduces a functional group that serves as the active center for sequential conjugation
What happens during phase II?
conjugation reactions, which involves the enzyme-catalyzed combination of a drug with an endogenous substance
What is required in phase II reactions?
- a functional group
- active center - as the site of conjugation with the endogenous substance
- energy indirectly for the synthesis of activated carriers, the form of the endogenous substance used in the conugation reaction
What are the enzymes catalyzing phase I biotransformation reactions?
cytochrome P450
aldehyde and alcohol dehydrogenases
deaminases
esterases
amidases
epoxide hydratase
What are the enzymes catalyzing phase II biotransformation reactions?
glucoronyl transferase
sulfotransferase
transacylases
acetylases
ethylases
methylases
glutathione transferase
Whare can you finds the enzymes catalyzing phase I and II?
in multiple tissues and some in the palsma
What is subcellular locations?
cytosol
mitochondria
endoplasmic reticulum
Where are the enzymes that are inducible by drugs located?
endoplasmic reticulum
What reactions does cytochrome P-450 catalyze?
- aromatic and aliphatic hydroxylations
- dealkylations at nitrogen, sulphur, and oxygen atoms
- heteroatom oxidations at nitrogen and sulphur atoms
- reductions at nitrogen atoms
Which subfamily of cytochrome is responsible for half of the total CYP450 in the liver?
CYP3A
which enzyme of the subfamily CYP3A is most abundant?
4
what is the mechanism of reaction of CYP450?
drug is oxidized and oxygen is reduced to water
reducing equivalents are provided by NADPH - generation of this cofactor is coupled to CYP450 reductase
what are some important genetic polymorphism in CYP450?
CYP2C and CYP2D is important in humasn
there are differences between racial and ethnic groups
what can be an inductor?
drugs and endogenous substances-hormones
what is metabolic tolerance?
when a drug induces its own metabolism
In what ways can CYP450 be inhibited?
competitive or non-competitive
What can cause inhibition of CYP450?
drugs: cimitidine, fluconazole, fluoxetine, erthromycin
some drugs that inhibit CYP3A4 can also inhibit…?
drug effluc ttransporter P-glycoprotein
What are the general feautures of glucoronyl transferase?
set of enzymes with overlapping specificities
involved in phase II reactions
catalyzes the conjugation of glucuronic acid to a variety of active centers - OH, COOH, SH and NH2
What is the mechanism of reaction of glucoronyl transferase?
UDP-glucoronic acid, the active glucoronide donor is formed from UTP and glucose-1P
it will then catalyzr the conjugation to the active center of the drug
where is glucoronyl transferase located?
in the endoplasmic reticulum
how is the glucoronyl trransferace induced?
only phase II reaction that is inducible by drugs and is a possible site of drug interactions
