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Y3 Med drug disposition > Conjugation Reactions > Flashcards

Conjugation Reactions Flashcards

1
Q

What phase of metabolism is oxidation (cytochrome P450)?

A

PHASE 1 metabolic reaction: metabolite formed with certain functional groups

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2
Q

What phase is glucuronidation?

A

(Conjugation reaction): PHASE 2 metabolic reaction

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3
Q

What phase follows phases 1 and 2?

A

Excretion (biliary or renally)

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4
Q

What do phase 2 reactions require?

A

They require a functional group as a site for conjugation (often phase 1 metabolite)

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5
Q

Describe what a drug undergoes in the hepatocyte.

A
  • Drug present in blood
  • Transporters facilitate uptake into the cell for metabolism
  • Follows either phase 1 or phase 2
  • Transporters for elimination
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6
Q

What type of molecules are conjugating molecules?

A

Endogenous - glucose or amino acid derivatives

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7
Q

What physicochemical properties do resulting conjugates have?

A

They are extremely polar (pka <3), terminal metabolites (not going to be metabolised further)

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8
Q

What is biliary and renal excretion of conjugates facilitated by?

A

Facilitated via efflux transporters (e.g. MRP2, MRP4)

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9
Q

Where are glucuronides formed?

A

In the liver

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10
Q

o Some Glucuronides are present in blood in systemic circulation – how do they get there if they’re formed in the liver?

A

MRP3 and MRP4 on side of hepatocyte efflux glucuronide into systemic circulation. Once it is in systemic circulation, it can be excreted via the kidneys

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11
Q

What is the general principle metabolism reactions follow?

A

Drug with certain functional group (e.g. COOH)

+

Endogenous compound (e.g. glucuronic acid)

–>

Conjugate (e.g. glucuronide)

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12
Q

What are the types of conjugation reactions?

A
  • direct conjugation

- conjugation of the phase 1 metabolite

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13
Q

What is direct conjugation?

A
  • often parallel reaction to CYP metabolism: diclofenac, propofol
  • already HAVE particular groups in their structure needed for conjugation
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14
Q

What phase 2 reactions occur with OH functional group?

A

Glucuronidation or Sulphation

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15
Q

What phase 2 reactions occur with COOH functional group?

A

Glucuronidation or Glycine conjugation

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16
Q

What phase 2 reactions occur with NH2 functional group?

A

Glucuronidation or Acetylation

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17
Q

What is a common mechanism for the activation step of conjugating agents?

A
  1. Conjugating agent gets activated as a coenzyme (for glucuronides, sulphates and acetyl conjugates) OR
  2. Drug (for amino acid conjugates) - complex, involves intermediary metabolism. Reactive intermediates - co-enzymes or co-substrates
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18
Q

What is a common mechanism for the synthetic step?

A

(Simple, transferase enzymes)

1. Enzymes transfer conjugate to molecule and a metabolite is formed

19
Q

What enzymes facilitate glucuronidation?

A

UGT enzymes (UDP-glucuronosyltransferases)

20
Q

Where are UGT enzymes located?

A

• UGT enzymes located on luminal side of the endoplasmic reticulum – membrane bound.
Present mainly in the liver, but also in the intestine and kidney

21
Q

What catalyses the addition of glucuronic acid to a substrate to form glucuronide metabolite?

A

Glycoproteins

22
Q

What is glucuronic acid a derivative of?

A

Glucose - readily available in the body

23
Q

Are conjugate metabolites generally active or inactive?

A

As they are terminal metabolites that are going to be eliminated, they are generally inactive*

*exceptions: morphine 6-glucuronide, ezetimibe glucuronide

24
Q

What drugs are conjugation metabolic pathways most important for?

A

Lamotrigine, mycophenolic acid, valproic acid (epileptic drugs glucuronidated)

25
Q

What glucuronides cause renal toxicity?

A

acyl glucuronides of NSAIDs

26
Q

What glucuronides contribute towards DDIs?

A

gemfibrozil glucuronide (inhibitor of OATP1B1 and CYP2C8)

27
Q

What compounds do UGTs conjugate?

A

Multiple endogenous compounds - bilirubin, steroid hormones, thyroxine and bile acids

28
Q

What is the difference in levels of UGT between adults and babies?

A

o New-born baby does not have some levels of enzymes
o UGT1A1 activity and protein expression reach adult levels at 3-6 months of age
o Morphine glucuronidation (UGT2B7) deficient in young infants

29
Q

What is congenital jaundice?

A

Increase in bilirubin levels that have not been conjugated (UGT1A1)

30
Q

What is Gilbert’s syndrome?

A

Unconjugated hyperbilirubinemia, deficiency in UGT1A1 in adults (UGT1A1*28)
o Occurs in 2-13% of Caucasian

31
Q

What are patients with UGT1A1*28 variant associated with?

A

Associated with higher risk of neutropenia (low neutrophils) as a side effect when receiving irinotecan

32
Q

What is Irinotecan disposition?

A
  • Does undergo some P450 metabolism which form the inactive metabolites
  • Forms SN-38: ACTIVE METABOLITE – glucuronidated via UGT1A1 etc
  • Build up of UGT1A1*2B leads to higher risk of neutropenia – therefore start at lower dose
33
Q

What UGT enzymes are the most abundant glucuronidation enzymes in both healthy kidneys and tumour tissue?

A

UGT1A9, UGT2B7 and UGT1A6

reduced renal glucuronidation in tumours

34
Q

What glucuronidation is seen in obese patients?

A

Increased

35
Q

What enzymes facilitate sulphation reactions?

A

SULT - sulphur transferase

36
Q

Where are SULT enzymes located?

A

Mainly in the cytosol - in contrast to membrane-bound UGTs.
Present in the liver and small intestine (SULT1A1)

*o SULT1A3 expressed in the human foetal liver

37
Q

Is an activation step required for SULT enzymes?

A

YES - via ATP, cofactor PAPS (3’phosphoadenosine 5’-phosphate). More readily saturable than UGTs: – concentration of PAPS is app. 10-fold < UDPGA

38
Q

What drugs do SULT enzymes metabolise?

A

Paracetamol, salbutamol and troglitazone

39
Q

What are SULT linked to the hepatoxicity of ?

A

some drugs e.g. troglitazone

40
Q

What is Glycine conjugation limited to?

A

Limited to acids: drug becomes activated as acyl coenzyme A intermediate

41
Q

What is Acetylation limited to?

A

Limited to amines: formation of N-acetyl conjugates.

  • acetyl CoA is the coenzyme
  • Genetic polymorphisms in N-acetyl transferase (NAT)
    - Rapid and slow acetylators (sulfasalazine)
42
Q

What is a phase 3 reaction: conjugate hydrolysis and enterohepatic recycling?

A

Form glucuronide but then if it gets excreted into the bile and goes into the intestine, it can get hydrolysed and converted back to the parent via enzymes.

  • this causes recycling of the parent molecule and prolonging the potential effect of the drug
  • occurs in the small intestine
43
Q

What enzymes are used in phase 3 reactions?

A 
o Beta-gluronidase (for glucuronide metabolites)
o Sulphatase (for sulphate metabolites)

Y3 Med drug disposition (12 decks)

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