L25 - liver metabolism Flashcards
what is elimination?
remove of substance or termination of it’s biological action
2 types of elimination
- metabolism
- excretion
metabolism
anabolism (build up) and catabolism (breakdown)
excretion
- kidneys excrete urine
- the faecal route
what is elimination carried out by?
- liver
- kidneys
- lungs
what do endogenous and ingested molecules reach liver through?
hepatic artery and portal vein
where are some endogenous and ingested molecules secreted into?
- into bile
- but most is reabsorbed into SI
what are most lipophilic molecules metabolised by?
liver enzymes to form polar molecules with can be excreted in urine
phase I reaction of metabolism
- catabolism: oxidation, reduction, hydrolysis
- products can be “still” or “even more” reactive
- new functional groups (e.g OH) to provide point of conjugation
- reaction done by haptic microsomal enzymes on SER inside hepatocytes
- microsomal enzymes apart of cytochrome P450 family
cytochrome p450 monooxygenase system
- 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
the monooxygenase P450 cycle
- 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
Phase II Reactions
- 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
pre-systematic first pass metabolism
- 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
active or toxic metabolites
pro drugs - drugs which become active once metabolised by microsomal enzymes
what does aspirin inhibit?
platelet function, it is inflammatory
cyclophosphamide metabolites are?
toxic
polymorphic variation in cyp450 enzymes
- single nucleotide polymorphisms (SNPs)
- giving rise to different polymorphic forms which metabolise at different rates
effect of fast metaboliser with an active drug?
drug becomes toxic or less effective
effect of fast metaboliser with a prodrug?
become active faster:??? not sure if this is right answer
common agents which affect CYP450
- inducers: brussel sprouts, smoking, wort
- inhibitors: grapefruit juice
enzyme inducers
- drugs can increase activity of CYP enzymes
- affecting the metabolism of other compounds/drug
useful enzymes in drug interactions
glucuronyl transferase given to premature babies to increase conjugation + remove bilirubin
harmful drugs in drug interactions
co administered drugs can be metabolised too quickly reducing effect, toxic metabolites can be increased
what are paracetamol metabolites (NAPQI)?
highly hepatotoxic
