PHASE I AND PHASE II METABOLISM Flashcards Preview

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Flashcards in PHASE I AND PHASE II METABOLISM Deck (15)
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1
Q

What is metabolism

A

Converting to a less pharmacologically active substance

  • May end up being more active
  • May end up being toxic/carcinogenic
2
Q

Phase I metabolism

A
  • Convert compount to more polar hydrophilic by adding or unmasking a functional group (-OH, -SH, -NH2, -COOH)
  • If sufficiently polar they may be excreted in the urine
  • May need to undergo phase 2 metabolism
3
Q

Phase II metabolism

A
  • Conjugation with endogenous substance = Increase aqueous solubility
  • Conjugation with glucuronice, sulfate, acetate, amino acid
4
Q

Phase I reactions

A
  • Oxidation, reduction, hydrolytic cleavage, alkylation, dealkylation, ring cyclization, n-carboxylation, dimerization, transamidation, isomerisation, decarboxylation
5
Q

Cytochrome P450

A
  • Absorbs light at 450nm when complexed with CO
  • Hemoprotein containing iron atom alternating between Fe2+ and Fe3+
  • Electron acceptor
  • 18 families and 43 subfamilies
  • Catalyses reactions to split molecular oxygen where one is introduced into drug and the other leaves as water
  • CYP3A4 is responsible for most drugs metabolism
6
Q

Flavin containing monooxygenase system

A
  • Mainly in liver but may be in gut + lungs
  • Located in SER (smooth endoplasmic reticulum)
  • Oxidises compounds containing sulfur and nitrogen
  • Use NADH and NADPH as cofactors
    1. Drug-H+O2+NADPH+H+>Drug-OH+NADP+H2O
7
Q

Structures prone to reduction

A
By reductase:
- Nitro 
- Azo
- Carbonyl
By hydrolysis (by esterases and peptidases):
- Esters
- Amide
8
Q

Structures prone to oxidation

A
  • N-methyl
  • Aromatic rings
  • Terminal positions of alkyl chains
  • Least hindered position of alicyclic rings
9
Q

Epoxide formation

A

For benzene, two routes:

  1. Hydride shift where para position to R is favoured = more hydrophilic/more capable of being conjugated in phase 2
  2. Epoxide hydrolase converts to a diol = more soluble in water and gets excreted in urine
    - Epoxides are alkylating agents making them toxic
    - Neighbouring carbons to O are very electrophilic allowing nucleobases and nucleophilic bases to react
    - Breaking these bonds are difficult
    - Can lead to mutations-cancers/other diseases
10
Q

NAPQI

A

Unwanted product formed by metabolism of paracetamol

  • Conjugated ketone / alpha beta unsaturated ketone
  • very electrophilic
  • reacts strongly with nucleophiles
  • can alkylate nucleophiles
  • N7 of guanine can react
  • Rearomatisation of that ring system makes C-N bond stronger and more difficult to remove
11
Q

Glucuronidation

A
  • By UDP-glucuronosyltransferase
  • On -OH, -SH, -NH2, -COOH groups
  • Products often excreted in bile (may enter enterohepatic circulation)
  • Can occur with amines, amides and sulfonamides
12
Q

Sulfoconjugation

A
  • Facilitated by sulfotransferases
  • For phenols, alcohols, amines and thiols
  • Sulfation and glucuronidation are competing pathways
13
Q

Acetylation

A
  • Facilitated by N-acetyltransferases
  • requires cofactor acetly-coA
  • Common reaction for aromatic amines and sulfonamides
  • Takes place in liver
  • acetyl-sulfonamide may be less soluble than parent compound causing renal toxicity due to precipitation in kidneys
14
Q

Amino acid conjugation

A
  • ATP dependent acetyl coA synthetase and CoASH forms active AMP-drug coA-drug
  • This then reacts with amino acid by N-acetylation
15
Q

Glutathione

A
  • Conjugated by glutathione-S-transferase
  • Removes potentially toxic compounds
  • Conjugated compound attacked by peptidase forming cysteine
  • This can be further acetylated for form N-acetylcysteine conjugate
  • Can react with NAPQI, Epoxodes, Alkyl halides, alpha beta unsaturated groups