Flashcards in METABOLISM Deck (32):
what is the definition of biotransformation or metabolism.
A change in the chemical structure of an absorbed drug within a living organism, usually by enzyme-catalyzed reactions.
what is the evolved purpose of the liver?
to process toxic substances from the diet and to process wastes from a variety of metabolic pathways. (it treats drugs the same way).
why is drug metabolism important?
enzumes play a role in terminating drug action, they make drugs more excretable and inactivates many drugs.
what kind of compounds are more readily excreted in urine and bile?
what does metabolism often results to in terms of compounds?
they inactivate compounds
why are certain drugs administered as inactive prodrugs?
because few drugs are activated by metabolism
why are lipid-soluble drugs not readily excreted from the body?
they cross out of renal tubules through membranes and back into the blood.
where are drugs metabolized?
the liver is the major site of metabolism of xenobiotics. Metabolism also occurs in other organs as well.
biotransformation reactions are catalyzed by cellular enzymes that are located in which sections? (order of likely hood)
endoplasmic reticulum> cytoplasm> mitochondria > nuclear/cell membrane > lysosomes.
where are drug metabolizing enzymes mainly found?
in the microsomes and in the cytosol.
what are microsomes?
they are vesicles consisting of membranes of ER which contain membrane-bound P45- enzymes (phase 1 metabolism)
what is cytosol?
supernatant consisting of cytoplasmic fluid and soluble phase 2
what are the two phases in which enzyme reactions are involved in drug metabolism?
phase 1 reactions : drugs are converter to more polar metabolites then either excreted or onto phase 2.
Phase 2 reactions: 'conjugation' or 'synthesis' reactions in which a substance from the diet is attached to the functional group derived from phase 1 reactions.
what are the 5 characteristics of phase 1 reactions?
1. makes drugs more reactive and capable of combining with polar conjugating groups.
2. substrates are lipid-soluble compounds of widely varied chemical structure.
3. metabolites are more water-soluble, can be circulated, excreted or undergo a phase 2 reaction.
4. involves one or more cytochrom P-450
5. P-450 heme-containig proteins that macimally absorbs light at 450 nm
what are other other names for the P-450 enzyme?
microsomal or CYP enzyme system; mixed-function oxidases (MFO)
what are the 5 steps to the cytochrom p450 cycle in drug oxidations?
1. Fe3+ is oxididze, and Fe2+ is reduced.
2. oxidized from combines with drug
3. NADPH-dependent cytochrome P450 reductase reduces p450
4. molecular oxygen is reduces to activated oxygen ->oxidized drug complex
5. activated oxygen is transferred to drug substrate to from oxidized product
what ate the 3 types of phase 1 reactions?
1. oxidation (LEO says GER)
these reactions introduce or unmask functional groups.
what are 3 characteristics of the phase 2 reactions?
1. couple drug with substrates from diet to produce conjugates
2. conjugates are often polar, inactive and readily excretable
3. some conjugating substances are glucuronic acid, sulfate, glutathione, methyl groups, glycine...
what are the 4 types of phase 2 reactions?
1. glucuronic acid conjugation
2. sulphate conjugation
4. glutathione conjugation
describe clucuronic acid conjugation.
very important pathway
large drugs are excreted into bile for elimination in feces, but glucuronidases in gut bacteria can hydrolyze conjugate and free drug, which can be reabsorbed (enteroheptic recirculation)
for people who are deficient in this enzyme, they are slow to metabolize certain drugs
give examples of sulphate conjugation
phenols and alcohols conjugated to sulphase (eg: acetaminophen)
it occurs in drugs with -NH2 group conjugated to COCH3 (eg. sulfonamide antimicrobial drugs)
describe glutathione conjugation.
epoxides, arene oxides conjugated to glutathione (eg anticancer drugs)
how can we counter act an acetaminophen overdose?
within limits, glutathione conjugation can inactive the reactive intermediate (NAPQI) -> physician will administer a source of glutathione (n-acetylcysteine) -> minimizes hepatic damage.
what are 6 factors that can affect the rate of drug metabolism?
1. enzyme induction and inhibition
2. multidrug therapy
describe the process of induction of drug metabolism
it increases drug metabolism and intrun decreases drug action. it can also increase the drug-related toxicity depending on whether phase 1 or 2 enzyme are induced. (note balance between phase 1 and 2 is important.
describe the process of inhibition of drug metabolism.
certain drugs can inhibit P450 activity mostly by competing fcor the same enzyme. eg some antifungal, antibiotics inhibit enzymes responsible for the metabolism of terfenadine.
describe the process of multi-drug therapy.
because there is a finite number of hepatic enzymes, the system can be saturated, and this is most common when multiple drugs require the same metabolic enzyme, and they are taken at the same time. The drugs then compete for, or inhibit, the metabolizing enzymes.
describe a possible distribution problem, in the body, which may inhibit metabolism.
drugs bound to plasma proteins or stored in fat are not available for metabolism.
describe how age may affect drug metabolism.
infants and older people may be deficient in metabolic capacity, or may even have over production of certain metabolic enzymes.
how can genetics effect the metabolism process?
process may very due to genetic polymorphism. eg CYP2D6 deficiency leads to a decrease in metabolism of some cardia drugs.