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
what are the key points of this lecture?
- 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
