PHARM 5: Drug Metabolism Flashcards
Why do we need metabolism?
- drugs tend to be lipophilic
- so lipid soluble drugs must be metabolized –> to become more water soluble –> so they can be excreted easily.
- metabolism eliminates/ reduces pharmacological + toxicological activity.
- and converts drug into something more polar + soluble
- -> more easily excreted by the kidneys
Where is the major organ for drug metabolism?
- LIVER
What is Hepatic First Pass Metabolism?
Hepatic First Pass Metabolism = metabolic conversion of drug into something different, before drug enters general circulation
What happens if a drug undergoes extensive first pass metabolism?
- low bioavailability
—> option: give drug intravenously
list briefly the stages of metabolic change
Phase I
Phase II
Excretion
- but some drug undergo only phase 1 / 2
Describe Phase 1 reactions?
PHASE 1 = releasing/ making functional groups
- oxidation/reduction CREATES new functional groups
- hydrolysis UNMASKS functions groups
- functional groups serves as pt of attachment for Phase II reactions
- little change in polarity
–> prepared drugs for Phase 2 metabolism by introducing functional group
Where does Phase I reactions primarily occur?
why?
- in the liver
- contains enzyme system cytochrome P450
- which has capability to metabolize lots of xenobiotics
What is the cytochrome P450 enzyme system?
- main system involved in Phase I oxidizing reactions
- predominantly found in liver
- also involved in metabolism of endogenous compounds such as steroid/ estrogens
note: some drugs can inhibit/induce CYP450
Give the reaction equation for cytochrome P450 mediated oxidation.
RH + NADPH + O2 + H+ –(cytochrome P450) —> ROH + NADP+ + H2O
in: drug, NADPH (reducing agent), molecular oxygen, source of protons.
out: oxidized drug, NADP+, Water
Describe the process of CYP450 oxidation.
- all P450 enzymes have porphyrin ring + iron at its active site
- drug binds to iron in catalytic site + reacts
- electron = donated by NADPH
- e- = picked up iron
- Fe3+ –> reduced to Fe2+
- Then oxygen binds to the catalytic side
- Then Fe2+ loses an e-
- becomes Fe3+
- oxygen picks up extra electron –> becomes unstable
- 2nd e- donated by NADPH
- e- picked up by Fe3+ –> Fe2+
- Fe2+ donates e- to O2 so oxygen is very unstable –> ready to reach
- Then drug is converted into hydroxylated derivative
and reactive oxygen is lost as water by picking up 2H+ - drug is released
- P450 returns to cycle with Fe3+ to undergo next cycle
note: oxidation reaction involves hydroxylation step catalyzed by P450 system.
What are characteristics of Phase II metabolism conjugated products?
conjugate formed:
- almost always inactive
- less lipid soluble
- more polar
- easier to excrete
What is the most common phase 2 metabolism reaction ?
GLUCURONIDATION
- addition of sugar to a foreign compound.
Describe Glutathione conjugation
- Glutathione reacts with electrophiles
- electrophiles damage DNA + proteins so they must be removed.
Explain Glucuronidation of ibuprofen.
a) What is the conjugating agent?
b) What is it catalyzed by?
c) what does it form?
Ibuprofen
a) conjugating agent = UDPGA
b) catalyzed by = Glucuronyl Transferase
c) –> to form sugar derivative of xenobiotic
derivative = polar (so can be removed)
Explain acetylation.
- if drug has amino group
- high energy intermediate = acetyl coA
- it is catalyzed by acetyl transferase
- acetylated derivation of drug + coA goes into intermediary metabolism.
Explain Methylation.
what is the high energy intermediate?
What is enzyme used?
- RZH + S-adenosylmethionine –> RZ-CH3 + S-adenosythomocysteine
- high energy intermediate = S-adenosyl methionine
- enzyme = methyl transferase
- methyl group on sulphur of S-adenosylmethionine = transferred to NH2 of NA –> to generate Adrenaline (the methylated derivative)
-
What is the effect of methylation?
- it decreases polarity
What is sulphation?
what are characteristics of the derivatives?
what is it catalyzed by?
- PAPS = sulfate donor
- xenobiotic is taken with PAPS
- xenobiotic gets sulfated to produce sulfuric acid derivative of the molecule
- derivative characteristics = very polar + water soluble
- catalyzed by: sulfotranferases
Describe conjugation with glutathione.
what is it catalyzed by?
RX + GSH —> R-SG + XH
- ## catalyzed by glutathione transferase
Why does the body have lots of glutathione?
- important to protect body from toxic metabolites
Glutathione is a tripeptide.
what does it consist of ?
what is the most important part of the molecule + why?
- glycine
- glutamine
- cysteine
most important = cysteine
- because it has the thiol
- which is the part that reacts
What are the 5 Phase II reactions?
- Glucuronidation
- Sulphation
- Acetylation
- Methylation
- Conjugation with a.acids / glutathione
What is a key characteristic of Phase II reactions?
- involves a high energy intermediate
e. g UDPGA/ PAPS
Give 5 reasons of the importance of drug metabolism
- biological half life of the chemical is decreased
- duration of exposure is reduced
- accumulation of compound is avoided
- duration of biological activity of chemical can be altered
- pharmacology/toxicology of the drug can be governed by its metabolism.
note: after phase 1 –> not v soluble
after phase 2 –> more soluble
-
note: enzymes involved in metabolism –> 9/10 times usually CYP450 enzyme
-
why do u not see acetanilide in pharmacy although it is a pro rug of paracetamol
it is toxic to blood cells
What happens in the oxidation of imipramine?
- N demethylation
- N methyl groups are oxidized
to form desimipramine
What happens in the oxidation of Codeine
- O demethylation
- O methyl groups are oxidized
to form Morphine
- N oxidation can also occur
-
note: diff individuals have diff levels of CYP450
-
tri methylinine (fish odor ) –> metabolized to something that is odorless occurs through what type of oxidation?
occurs via N - oxidation
describe alcohol oxidation.
what enzymes are used?
- ethanol –> acetaldehyde –> acetic acid
enzyme: cytoplasmic alcohol dehydrogenase
Glucuronidation is catalyzed by what enzyme?
Glucuronyl transferase
Methylation is catalyzed by what enzyme?
Methyl Transferase
What is the conjugating agent used in the process of glucuronidation?
UDPGA
