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Drug Disposition > Conjugation reactions > Flashcards

Conjugation reactions Flashcards

1
Q

General points of conjugation reactions?

A
  • functional group required for conjugation
  • conjugation molecules are endogenous compounds
  • resulting conjugates are extremely polar and usually terminal metabolites
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2
Q

How are conjugates excreted?

A

Biliary and renal excretion, facilitated by efflux transporters

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3
Q

Approx pKa of resulting conjugates?

A

< 3

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4
Q

What are the two types of conjugation reactions?

A
  • direct conjugation of the drug (often parallel to CYP metabolism, e.g. diclofenac, propofol
  • conjugation of drug metabolites
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5
Q

What functional groups can glucuronidation occur at?

A

-OH, -COOH, -NH2

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6
Q

What types of conjugation can occur at -OH groups?

A

glucuronidation or sulphation

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7
Q

What types of conjugation can occur at -COOH groups?

A

glucuronidation or glycine conjugation

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8
Q

What types of conjugation can occur at -NH2 groups?

A

glucuronidation or acetylation

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9
Q

Pathways of midazolam metabolism?

A

hydroxylation (aliphatic or aromatic) - CYP mediated. can then be glucuronidated

alternatively - N-glucuronidation

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10
Q

Pathways of naloxone metabolism?

A

Glucuronidation of -OH

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11
Q

What are the two steps of conjugation reactions?

A
  1. Activation step

2. Synthetic step

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12
Q

What happens in the first step of conjugation?

A

activation of the conjugating agent (glucuronides, sulphation or acetyl conjugates) or the drug (amino acid conjugates)

complex and involves intermediary metabolism

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13
Q

What happens in the second step of conjugation?

A

simple - transferase enzymes involved

activated co-enzyme (or drug) combined with the drug (or co-substrate) to form the conjugate

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14
Q

What does UGT stand for?

A

UDP-glucuronosyltransferases

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15
Q

Where are in the cell are UGTs located?

A

luminal side of endoplasmic reticulum (different to CYP450s as not membrane bound)

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16
Q

Function of UGTs?

A

glycoproteins that catalyse the addition of glucuronic acid to a substrate

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17
Q

How many human UGTs are there?

A

22

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18
Q

Which UGT subfamilies are the most relevant?

A

1A and 2B

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19
Q

Where in the body are UGTs located?

A

predominantly liver, but also intestine and kidneys

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20
Q

Clinical importance of conjugation reactions?

A

approx 40% of top prescribed drugs are metabolised by UGTs

21
Q

Example of drugs metabolised by glucuronidation?

A

Lamotrigine, mycophenolic acid, valproic acid

22
Q

Example of endogenous compounds metabolised by glucuronidation?

A

bilirubin, steroid hormones, thyroxine, bile acids

23
Q

Which glucuronide metabolites are pharmacologically active?

A

morphine-6 glucuronide, ezetimibe glucuronide

quite rare, most are terminal

24
Q

How can glucuronides contribute to DDIs?

A

inhibit transporters or metabolic enzymes

25
Q

How does gemfibrozil cause DDIs?

A

glucuronide metabolite is a potent inhibitor of CYP2C8 and OATP1B1

26
Q

How does UGT expression vary between adults and children?

A

UGT1A1 activity and expression reach adult levels at 3-6 months old (newborns have far less glucuronidation activity)
cause of congenital jaundice - increased bilirubin

27
Q

Which enzyme glucuronidates morphine?

A

UGT2B7

28
Q

Neonates and UGT2B7?

A

have reduced activity so reduced metabolism of morphine

29
Q

What is Gilbert’s syndrome?

A

UGT1A1 deficiency, which leads to unconjugated hyperbilirubinaemia
UGT1A1*28 - the polymorphism allelic variant
2-13% of caucasians

30
Q

Risks of the UGT1A1*28 variant?

A

increased risk of neutropaeia when receiving irinotecan (lower starting dose recommended)

no glucuronidation so higher side effects

31
Q

Mycophenolic acid inter-individual variability?

A

Different genotype groups have a significant impact on UGT activity and therefore PK/PD - significant variability found in paediatric transplant patients. can affect organ reception

32
Q

Which glucuronidation enzymes are the most abundant in the kidneys?

A

UGT1A9, 2B7, 1B6

33
Q

Glucuronidation in obese patients?

A

Reported increased glucuronidation in morbidly obese

34
Q

GLucuronidation in CKD?

A

Evidence for uremic toxins inhibiting UGT1A9 and 2B7

35
Q

What do SULT enzymes do?

A

Sulphation

36
Q

Where are SULT enzymes located in the cell?

A

Cytosol

37
Q

Relationship between UGTs and SULTs?

A

Similar, so often have the same substrates. SULTs far more readily saturated than UGTs

38
Q

Where in the body are SULTs located?

A

Liver and small intestine (SULT1A1)

39
Q

Examples of drugs metabolised by SULTs?

A

paracetamol, salbutamol, troglitazone

40
Q

What SULT is expressed in human feotuses?

A

SULT1A3

41
Q

SULTs and hepatotoxicity?

A

Some sulphate metabolites are linked to hepatotoxicity - e.g. troglitazone

42
Q

What are the parallel pathways of paracetamol metabolism?

A
  • CYP mediated N-hydroxylation and rearrangment
  • Sulfation
  • Glucuronidation
43
Q

What happens in glycine conjugation?

A

Drug becomes activated with acyl coenzyme A intermediate

44
Q

What happens in acetylation?

A
  • limited to amines, formation of N-acetyl conjugates

- Acetyl CoA is coenzyme

45
Q

Which enzyme catalyses acetylation reactions?

A

N-acetyl transferase (NAT)

46
Q

Polymorphisms of NAT and the consequences?

A

get rapid and slow metabolisers

- clinically relevant in patients taking sulfasalazine

47
Q

What are Phase III reactions?

A

Hydrolysis of conjugates

48
Q

Which enzymes carry out phase III reactions?

A

glucuronidase (glucuronides)

Sulphatase (for sulphates)

49
Q

Where to phase III reactions occur?

A

small intestine - metabolites excreted via biliary excretion of metabolites, which can then be enterohepatically recycled and prolong drug effect

Drug Disposition (11 decks)

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