Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
Convert drugs (usually lipid soluble) to metabolites (usually less lipid soluble and easier to excrete)
State the main aim of phase 1 and phase 2 metabolism
- Introduce a reactive group to the drug (with little/no increase in polarity)
- Add a water soluble conjugate to the reactive group
Describe the three types of reaction that fall under phase 1 metabolism
Oxidation (‘gaining oxygen/loss of electrons’) and Reduction (‘gaining hydrogen/electrons’) create new functional groups
Hydrolysis unmasks functional groups (and tends to split molecules in two)
Note: Most common Phase 1 metabolism = Oxidation (often start with hydroxylation)
Most oxidative metabolism of drugs is catalysed by which family of enzymes?
Cytochromes P450
57 enzymes
Found on the S.E.R. in hepatocytes
State the three possible types of phase 1 metabolites
Active parent drug => inert metabolite
Active parent drug => active metabolite (prolongs effects)
Inactive parent drug (prodrug) => active metabolite
What is the most common phase 2 metabolism and why?
Glucuronidation; low affinity/high capacity – more likely to occur at high drug dosages
State the 6 types of phase 2 reactions
- Glucuronidation
- Acetylation
- Sulphation
- Methylation
- Amino Acid Conjugation
- Glutathione Conjugation
State the conjugating agent and target functional group for Glutathione Conjugation
Glutathione Electrophiles (R=O)
State the conjugating agent and target functional group for Glucuronidation
UDP-glucuronic acid
(Nucleophiles) -OH, -COOH, -NH2, -SH
State the conjugating agent and target functional group for Acetylation
Acetyl CoA
-OH, -NH2 (usually aromatic amines; drug e.g. Isoniazid)
State the conjugating agent and target functional group for Sulphation
3’-phosphoadenosine-5’-phosphosulphate
-OH, -NH2
Describe the phase 2 metabolism of paracetamol
- 40-60% Sulphation (high affinity/low capacity - more likely to occur at low drug dosages)
- 20-30% glucuronidation
- 10% glutathione conjugation
How do you convert paracetamol to an electrophile, prior to glutathione conjugation?
Paracetamol is converted to the electrophile NAPQI, by losing two hydrogens and forming C=O and C=N, from C-OH and N-H respectively
Explain the problem of paracetamol overdose
Paracetamol overdose => glutathione stores overwhelmed => accumulation of NAPQI electrophiles which are extremely reactive and damaging
What is the conjugating agent/high energy intermediate for methylation? Give an example of a drug
S-adenosyl methionine
e.g. Levodopa
