#6 drug metabolism Flashcards
3 possible consequesnces of metabolic transformation
- inactivation
- activation
- maintenance of activity
inactivation
drugs are often converted to a more hydrophilic form which makes it less able to pass through membranes, less active and easier to excrete
location of phase I reactions
endoplasamic reticulum
location of phase II reactions
cytoplasm
Phase I reactions
make drug more hydrophilic (polar) by adding or uncovering a functional group to be used in phase II (-OH, -SH, -NH). After phase I the activity of the drug may be lower, equal, or even higher
phase II reactions
conjugation with endogenous substance on functional group added during phase I reaction. Decreases drug activity.
examples of substrates: glucuronic acid, sulfate, amino acids
if the drug already has a functional group it can skip phase I
Net effect of Phase I and II reactions
lipophilic drug is converted into a more hydrophilic metabolite that is easily eliminated in the urine
4 main phase I reactions
- microsomal oxidations
- non-microsomal oxidations
- reductions
- hydrolyses
microsomal oxidations main enzyme
CYTOCHROME P450 ENZYMES
family of enzymes (57 isoforms)
mainly found in endoplasmic reticulum (liver and intestine)
Mixed-function oxidase (MFO) system
NADPH-cytochrome P450 reductase
MICROSOMAL FRACTION
isolated by tissue homogenization and differential centrifugation
pellet - vesicles formed from ER membrane: MICROSOMES
useful for in vitro studies
assign P450 enzyme(s) to drug: PROMISCUITY
net effect of microsomal oxidation
one oxygen atom is incorporated into the drug and one into water by cytochrome P450 and NADPH-cytochrome P450 reductase
Non-microsomal oxidations
not mediated by cytochrome P450
example- alcohol oxidation (by alcohol dehydrogenase)
Hydrolysis reactions
also an oxidation reaction not mediated by P450
bonds are cleaved by the addition of H2O
Oxygen from the H2O is incorporated into the metabolite
Esterases & amidases
