L25 - liver metabolism

Question 1

what is elimination?

Answer 1

remove of substance or termination of it’s biological action

Question 2

2 types of elimination

Answer 2

1. metabolism
2. excretion

Question 3

metabolism

Answer 3

anabolism (build up) and catabolism (breakdown)

Question 4

excretion

Answer 4

• kidneys excrete urine
• the faecal route

Question 5

what is elimination carried out by?

Answer 5

• liver
• kidneys
• lungs

Question 6

what do endogenous and ingested molecules reach liver through?

Answer 6

hepatic artery and portal vein

Question 7

where are some endogenous and ingested molecules secreted into?

Answer 7

• into bile
• but most is reabsorbed into SI

Question 8

what are most lipophilic molecules metabolised by?

Answer 8

liver enzymes to form polar molecules with can be excreted in urine

Question 9

phase I reaction of metabolism

Answer 9

1. catabolism: oxidation, reduction, hydrolysis
2. products can be “still” or “even more” reactive
3. new functional groups (e.g OH) to provide point of conjugation
4. reaction done by haptic microsomal enzymes on SER inside hepatocytes
5. microsomal enzymes apart of cytochrome P450 family

Question 10

cytochrome p450 monooxygenase system

Answer 10

• family of haem enzymes
• diff members of family have diff letters + numbers
• differ in a.a sequence, substrate specificity, susceptibility to inducers + inhibitors
• species + inter individual variation

Question 11

the monooxygenase P450 cycle

Answer 11

• P450 contains fe3+
• this combines with drug
• receives electron from NADPH P450 reductase
• iron reduced to fe2+
• combines with O2, a proton, an electron to form FEOOH-DH
• this combines with H+ to form h2o and FeO3+DH
• this extract H+ ion to release DOH and regenerated P450

Question 12

Phase II Reactions

Answer 12

• anabolic
• involve conjugation (attachment of substituent group)
• inactive product
• carrier out by liver
• hydrophilic conjugates secreted into bile, delivered to SI
• where conjugation removed
• molecule is reabsorbed - enterohepatic recirculation

Question 13

pre-systematic first pass metabolism

Answer 13

• food + drugs entering gut absorbed into SI and pass into blood
• blood carried to liver by hepatic portal vein
• hepatic microsomal enzymes metabolise food + drugs before they enter systemic circulation

Question 14

active or toxic metabolites

Answer 14

pro drugs - drugs which become active once metabolised by microsomal enzymes

Question 15

what does aspirin inhibit?

Answer 15

platelet function, it is inflammatory

Question 16

cyclophosphamide metabolites are?

Answer 16

toxic

Question 17

polymorphic variation in cyp450 enzymes

Answer 17

• single nucleotide polymorphisms (SNPs)
• giving rise to different polymorphic forms which metabolise at different rates

Question 18

effect of fast metaboliser with an active drug?

Answer 18

drug becomes toxic or less effective

Question 19

effect of fast metaboliser with a prodrug?

Answer 19

become active faster:??? not sure if this is right answer

Question 20

common agents which affect CYP450

Answer 20

• inducers: brussel sprouts, smoking, wort
• inhibitors: grapefruit juice

Question 21

enzyme inducers

Answer 21

• drugs can increase activity of CYP enzymes
• affecting the metabolism of other compounds/drug

Question 22

useful enzymes in drug interactions

Answer 22

glucuronyl transferase given to premature babies to increase conjugation + remove bilirubin

Question 23

harmful drugs in drug interactions

Answer 23

co administered drugs can be metabolised too quickly reducing effect, toxic metabolites can be increased

Question 24

what are paracetamol metabolites (NAPQI)?

Answer 24

highly hepatotoxic

Question 25

what are the key points of this lecture?

Answer 25

• cyp450 liver microsomal enzyme used in drug metabolism
• phase I and II reactions aim to decrease lipid solubility + increase renal elimination
• so changes to liver function + enzyme activity have big effects on drug concentration + duration of action
• enzyme activity affected by genetic polymorphisms, diet, cooadministered drugs