F9 Absorption and metabolism of drugs

Question 1

what do the majority of drugs undergo after administration?

Answer 1

• multiple chemical changes in the body before they are excreted
• I.e. metabolism

Question 2

what is involved in the elimination of drugs from the body?

Answer 2

metabolism
excretion

Question 3

what ratio of elimination pathways are related to metabolism vs excretion?

Answer 3

70% related to metabolism
30% related to direct excretion

Question 4

what are the most common metabolic reactions on drug molecules?

Answer 4

oxidation
reduction
hydrolysis
different types of conjugations

Question 5

describe competitive metabolism. what does the fraction of drug molecules going into each metabolite depend on?

Answer 5

• drugs often undergo metabolism by several competing pathways simultaneously
• the fraction going to each metabolite depends on the relative rates of each of the parallel pathways

Question 6

give an example of a common secondary metabolism

Answer 6

oxidation, reduction and hydrolysis are often followed by a conjugation reaction

Question 7

what is meant by sequential metabolism?

Answer 7

when primary and secondary metabolism pathways happen in series

Question 8

in short, compare competitive and sequential metabolism

Answer 8

competitive
- different types of reaction can happen to a molecule at the same time

sequential
- reactions happen as a sequence of events on drug molecules

Question 9

in general, what does phase I and phase II mean in regards to metabolism pathways?

Answer 9

• the type of chemical change that occurs, not the order in which they happen
• phase II can happen alone or before phase I and vice-versa

Question 10

state some metabolic reactions that are commonly referred to as phase I and why

Answer 10

• oxidation
• reduction
• hydrolysis

this is because they often occur first but not always

Question 11

state some metabolic reactions that are commonly referred to as phase II and why

Answer 11

• conjugations

this is because they often occur second but not always

Question 12

what are phase I reactions commonly considered to be for? is this always the case?

Answer 12

• commonly considered to be a ‘preparation’ of the drug molecule for phase II reactions
• this is not an absolute rule because some drugs undergo primary elimination by phase II reactions and some undergo phase I metabolism without subsequent phase II reactions

Question 13

state a list of reactions of phase I metabolism

Answer 13

• oxidation (mediated and not mediated by CYP450 enzymes)
• reduction
• hydrolysis
• hydration
• isomerisation
• miscellaneous

Question 14

describe CYPP450-dependent mixed-function oxidation reactions

Answer 14

• most common phase I reaction
• catalyses the oxidation of thousands of diverse drugs and chemicals

Question 15

state a common property of the molecules metabolised in CYP450-dependent mixed-function oxidation reactions

Answer 15

usually have a reasonably high degree of lipophilicity

Question 16

what is the nomenclature for CYP450 enzymes (and other CYP enzymes) based on?

Answer 16

genetic sequence similarity

Question 17

describe the CYP3A sub-family of enzymes (not including their specific function)

Answer 17

• quantitatively the major sub-family of metabolism in human livers and intestinal wall
• CYP3A4 (major form) exhibits considerable inter-individuals variation in humans (polymorphism is mostly genetic based)

Question 18

describe the function of the CYP3A sub-family of enzymes

Answer 18

• metabolises many drugs of diverse structure and size
• found in the intestinal wall as well as the liver
• major player in intestinal first-pass metabolism

Question 19

compare the activity of the CYP3A sub-family in the small intestine and large intestine

Answer 19

• highest activity in the small intestine (especially duodenum)
• much less activity in the large intestine

Question 20

explain why there is fast and slow metaboliser variation between humans in terms of CYP enzymes

Answer 20

fast and slow metaboliser groups because of the CYP3A4 activity as well as other enzymes’ activities

Question 21

describe the relationship between abundance of CYP and its importance in drug metabolism. give an example to justify

Answer 21

• no relationship
• CYP2D6 makes up 2% of the total CYP content but is involved in 25% clearance of drugs

Question 22

state 9 types of oxidations involving CYP450

Answer 22

• aromatic hydroxylation
• aliphatic hydroxylation
• epoxidation
• dealkylations
• oxidative deamination
• dehalogenation
• N-oxidation and S-oxidation
• phosphothionate oxidation

Question 23

describe aromatic hydroxylation

Answer 23

• very common for drugs containing an aromatic ring
• addition of a hydroxyl group

Question 24

describe aliphatic hydroxylation

Answer 24

• very common
• addition of hydroxyl group to aliphatic chain

Question 25

describe epoxidation

Answer 25

epoxides are normally unstable intermediates but may be stable enough to be isolated from polycyclic compounds (lots of rings)

Question 26

describe dealkylation

Answer 26

removal of methyl groups (or other alkyl groups) from N, O or S atoms

Question 27

describe oxidative deamination

Answer 27

formation of the corresponding ketone and release of ammonium ions

Question 28

state 6 oxidations not catalysed by CYP450

Answer 28

- alcohol dehydrogenase - aldehyde dehydrogenase - xanthine oxidase - amine oxidases - aromatases - alkylhydrazine oxidases

Question 29

describe alcohol dehydrogenase

Answer 29

- catalyses the oxidation of many alcohols (including ethanol) to the corresponding aldehyde - is localised in the soluble fractions of liver, kidney and lung cells

Question 30

state 2 other phase I metabolism reactions that are not oxidations

Answer 30

- reductive metabolism - hydrolysis

Question 31

describe reductive metabolism

Answer 31

- of azo- and nitro- compounds - can both be reduced / mediated by CYP450 (but not only)

Question 32

state 2 types of hydrolysis in phase I metabolism and describe them

Answer 32

ester hydrolysis - in plasma (non-specific acetylcholine esterase and other enzymes) - or in liver (specific esterase for particular groups of compounds) amide hydrolysis - in plasma (slower than esters) - or by liver amidases (more likely)

Question 33

what does phase II metabolism usually lead to?

Answer 33

a more water-soluble product which can be excreted in bile or urine

Question 34

what are the main 2 reactions in case II metabolism?

Answer 34

glucuronidation sulfation

Question 35

describe glucuronidation as a phase II metabolic reaction

Answer 35

- conjugation with α-D-glucuronic acid - the major route of sugar conjugation and the most widespread of the conjugation reactions - certain drugs can be directly conjugated with glucuronic acid which bypasses the need for phase I metabolism

Question 36

what do O- and N-glucuronides form from?

Answer 36

O-glucuronides - phenols, alcohols (ether glucuronides) and carboxylic acids (ester glucuronides) N-glucuronides - amines, amides and sulfonamides

Question 37

describe sulfation as a phase II metabolic reaction

Answer 37

- a major conjugation pathway fro phenols but can also occur for alcohols, amines and thiols (lesser extent)

Question 38

describe how amino acid conjugation is different to other phase II metabolic reactions

Answer 38

- not a single reaction like the others - chain of reactions

Question 39

what is the main organ responsible for both phase I and II metabolism?

Answer 39

liver

Question 40

other than the liver, state some organs involved in phase I and II metabolic reactions

Answer 40

GIT kidney GIT flora lung blood brain placenta skin etc.

Question 41

what does drug localisation and metabolism depend on?

Answer 41

physicochemical properties of the drug - pKa - lipid solubility - molecular weight chemical composition of a metabolising organ presence of specific uptake mechanisms (transporters)

Question 42

for metabolism in cells, which 2 sub cellular organelles are the most important?

Answer 42

- endoplasmic reticulum (microsomes) - cytosol

Question 43

state a metabolic reaction that occurs in the endoplasmic reticulum of cells

Answer 43

glucuronidation

Question 44

state a metabolic reaction that occurs in the cytosol of cells

Answer 44

other types of conjugation (not glucuronidation)

Question 45

what enzymes are found in the endoplasmic reticulum for metabolism?

Answer 45

- phase I oxidative enzymes - phase Ii enzyme glucuronosyl transferase

Question 46

apart from the phase II enzyme 'glucuronosyl transferase', where are phase II enzymes mainly found in cells?

Answer 46

predominantly in the cytoplasm

Question 47

how is the amount of drug administered reduced before it reaches the general circulation? what is this called?

Answer 47

- first pass metabolism - metabolism during the first passage across the intestinal wall and through the liver - this is called first-pass metabolic loss

Question 48

why may an oral dose of a drug need to be larger than the equivalent IV dose?

Answer 48

- when metabolites formed during the first pass through the intestine wall and liver are inactive or less potent than the parent drug - higher dose required even if the drug is completely absorbed from the intestinal lumen

Question 49

explain the importance of intestinal first-pass metabolism on bioavailability using the example of simvastatin

Answer 49

- oral bioavailability is about 5% when taken with water - low bioavailability due to first pass metabolism in gut and liver (absorption is not a limiting factor) - oral bioavailability increased 3.6 fold when taken with grapefruit juice due to inhibition of enzymes at intestinal wall (not as much inhibition at liver)