Lecture 7 - General principles of drug metabolism Flashcards
Xenobiotic metabolism
def
Process by which foreign
compounds are metabolised in the
body to facilitate their elimination
how is a non-endogenous compound removed from body?
changed into polar (water soluble)
- then urine or bile
sum up enterohepatic circulation
recycling system for certain drugs and substances
prolongs drug action and delays elimination
describe pathway for enterohepatic circulation
from intestine to portal vein
liver proceses drug bile acids carry to intestine via gall bladder
can also go through systemic ciruclation to liver from portal vein
sites of metabolism
liver - MAIN
GI
kidney
skin
lung
plasma (hydrolysis)
brain
give the 5 functions of the liver metabolism
- detoxification
- metabolism of carbs , lipids & proteins
- synthesis of plasma proteins
- storage of glycogen , vitemins & minerals (Vit A & D)
- Bile production
Main liver cell type
hepatocytes
what can damaged cells be replaced by?
liver regeneration
what are most likely to be damaged by reactive metabolites?
- hepatocyte proliferation
- liver stem/progenitor cells
what does repeated damage and exhaustion of regeneration lead to?
fibrosis & cirrhosis
descirbe microsomal enzymes and what they do
drug metabolising enzymes found in smooth ER (main in liver cells)
- break down drugs for removal
- some drugs (barbiturates ) increase ER and enzyme levels
where are non- microsomal enzymes found ?
cytosol and mitochondria
what is a microsome?
tiny vesicle
formed when cells are broken up in lab
formed from the smooth ER
contains
- drug - metabolizing enzymes (CYP450)
- other enzymes
(DO NOT EXIST NATUALLY IN CELLS)
created in labs
descibe the 2 phases of drug metabolism
phase 1 and phase 2
1) mostly mediated by cytochrome p450 enzymes ( oxidation reduction hydroysis)
2) conjugation reactions
“3) drug transprort “
how does phase 1 metabolism modify drugs to make them more polar and easier to excrete ?
adding or exposing a functional group - making them more polar + easier to excrete
(CATABOLIC)
GIVE key phase 1 metabolism enzymes
cytochrome p450s
- oxidases
- esterases
- epoxide hydrolases
- dehydrogenases
key points of CYPS -450
57 types in humans - overlapping functions
- genetic differences affect how people process drugs
- can be induced or inhibited - affecting drug levels
what percentage of durgs is CYP3A4 responsible for metabolising?
50%
where is CYP450 most abundent ?
liver and gut
what does st johns wort do?
induction of CYP3A4 and P-gp
descibe gratefruit juice interaction w CYP3A4?
irreverible inhibition
describe phase 2 met ?
conjugation - detoxify compounds and prepare them for excretion
(ANABOLIC )
do compounds always undergo phase 1before phase 2?
no
when suitable functional groups for conjugation are already present on molecule reverse
common phase 2 metabolism reactions ?
- glucuronyl
- sulfate
- methyl
- acetyl
give the 4 letter phase 2 enzymes and 2 more
- UDP-glucuronosyltransferases (UGTs)
- Sulfotransferases (SULTs)
- Glutathione S-transferases (GSTs)
- N-acetyltransferases (NATs)
- Methyltransferases
- Amino acid conjugating enzymes (e.g. glycine and
glutamic acid)
what is aspirin first broken down tO?
salicylic acid - body then attaches glucuronide & sulfate to salicylic acid - water soluble
glucuronide x2 and glycline get saturated so have to go back to phase 1 metabolism oxidation
First pass metabolism in the liver and gut wall ____ the bioavailability of
drugs given PO
reduces
explain bioavailability
how much of a drug reaches blood stream
factors which can affect first pass metabolism
- genetic variations between induviduals in the liver and GI
- variations between induviduals in the liver and GI blood flow
- gut microbiota
whats a pro drug ?
administered as an inactive form and require metabolism to become active
examples of morphine
codeine -> morphine
(CYP2D6 demethylation)
Diacetyl- >morphine
(deacetylation)
cyclophosphamide -> 4-OH-CYPA
(hydroxylation)
