Metabolism Flashcards
How is being lipophilic both a negative and a positive in terms of drugs?
Positive: allows for molecule to diffuse across cell membranes and access target tissues
Negative: makes it hard for the body to eliminate the drugs after their use; because kidney reabsorption back into systemic circulation
Importance of biotransformation
The metabolism of drugs by enzymes to more water-soluble metabolites allows them to be excreted (urine, bile, feces)
What does a drug’s duration of action depend on?
duration of action is inversely proportional to the rate at which they are metabolically inactivated
What is the main determinant of a drugs half life?
Biotransformation of the drug
How are biotransformation reactions categorized?
- Phase 1
- Phase 2
Phase I biotransformation rxn
-Biotransformation enzymes modify the lipophilic drug molecule mainly by oxidation (adding an OH group, or exposing COOH and NH2) to make them more water soluble
Phase II biotransformation rxn
Synthetic rxns that conjugate the drug with a highly polar endogenous compound in the cell (eg. carbohydrate, sulphate, acetate) greatly increasing their water solubility
Which organ is the most important for drug biotranformation?
Liver!
Followed by lung, kidney, intestines. Then skin, testes, placenta, adrenals.
Why does the nervous system have very low metabolizing enzymes for drug biotransformation?
Because metabolizing enzymes can become dangerous molecules (such as ROS) so don’t want this to occur in nervous system
Most important Phase I biotransformation rxn
Oxidation
Important phase II biotransformation rxns
- Sulphation
- Glucuronidation
- Glutathione conjugation
- Acetylation
Cytochrome P450-dependent monooxygenases (CYPs)
-major phase I oxidative enzymes
Where are CYP enzymes located?
smooth ER
Simple example of Phase I biotransformation rxn (hydroxylation)
Drug (RH) + O2 + NADPH –> Metabolite (ROH) +H2O + NADP+
Other than biotransformation rxns, what else are CYPs used for?
Used in many catabolic and anabolic reactions involving endogenous compounds (eg. steroid hormones originally derived by cholesterol)
CYP enzyme family
-more than 100 different CYP enzymes
-have broad and overlapping substrate specificities
Define broad and overlapping in terms of substrate specificities
Broad: one enzyme can biotransform many drugs
Overlapping: one drug can be biotransformed by several enzymes
CYP causing bioactivation of a drug instead of inactivation
CYP enzymes can sometimes bioactivate a drug making them more pharmacologically or toxicologically active
Phenacetin and acetaminophen examples
CYP enzymes can bioactivate phenacetin, snipping the molecule forming an OH group= Acetaminophen
Parathion and paraoxon example
CYP enzymes can bioactivate parathion, adding an S group = Paraoxon
**Paraoxon is a strong inhibitor of acetylcholinesterase (stop signal for cholinergic pathways)
Hepatic portal venous system
-strategy to intercept and detoxify substances ingested (oral route)
-all substances are absorbed from the gut to the liver for biotransformation before they reach systemic circulation
First pass effect
Results in nearly complete inactivation (more than 90%) of certain drugs after oral ingestion
**Reason why certain drugs are not given orally and are administered via different routes
Oral bioavailability
The fraction of an orally administered drug that reaches the systemic circulation in an unchanged form
Bioavailability eqn
Bioavailability= AUC (oral) / AUC (IV)
AUC=area under curve
Curve= concentration of drug in blood over time
What molecules are being looked for during a blood test?
Phase II biotransformation molecules
Glucuronidation
-major phase II biotransformation pathyway in mammals
-enzymes for it located on smooth ER
Glucuronidation enzyme and cofactor
Enzyme: UDP-glucuronosyl transferase (UDP-GT or UGT)
Cofactor: UDP-glucuronic acid
Why should acetaminophen not be given to cats?
Cats have low levels of UDP-GT so they are unable to biotransform acetaminophen and rid it from the body
Sulfation enzyme and cofactor
Enzyme: sulfotransferase (ST)
Cofactor: PAPS
Acetylation enzyme and cofactor
Enzyme: N-acetyltransferase (NAT)
Cofactor: acetyl coenzyme A
Glutathione conjugation
-extremely important defense against ROS and epoxides
**1:100 O2 molecules are converted to superoxide radical
Glutathione conjugation enzyme and cofactor
Enzyme: Glutathione S transferase
Cofactor: Glutathione (GSH)
Factors influencing biotransformation
1.Enzyme induction and inhibition
2. Intraspecific differences
3. Interspecific differences
4. Sex and Age
5. Diet
6. Disease
Enzyme induction and inhibition
-CYP enzymes and phase 2 enzymes can all be induced and inhibited
- affects duration of drug action and inhibitions
-can also be affected by depletion of cofactors
Intraspecific differences
-genetic differences in the expression of enzymes= can lead to poor metabolizers or rapid metabolizers in the population
Ex. Alcohol dehydrogenase (ADH) in humans
Interspecific differences
-Difference animals have differences in biotransformations
-Cats poor glucuronidators (UDP-GT)
-Dogs poor acetylators (NAT)
-pigs poor sulfators (ST)
Sex and Age
-sex specific differences in certain CYP enzymes… often young and old individuals have lower enzyme activities
Diet
-certain dietary ingredients can induce or inhibit phase I or phase II enzymes
ex. grapefruit juice inhibits CYP3A4 in humans
Disease
-impaired liver or kidney function can decrease biotransformation and therefore excretion of drugs
