Drug Disposition II Flashcards
Drug metabolism results in: (3)
elimination/renal clearance
blood levels
effects
- A member of the cytochrome P450 (CYP) enzyme superfamily
- High levels in the liver
- Metabolizes many drugs
- Genetic polymorphims results in humans with
- “normal” enzyme activity
- very low activity (no effect of codeine)
- very high activity
CYP 2D6
which is a gene
Key information needed to predict drug metabolism in your patient (3)
- what enzymes metabolize
- genetic factors that affect enzyme
- drug activated or inactivated by metabolism
What are consequences of biotransformation? (2)
- Increased polarity (water solubility), which results in facilitated excretion
- Pharmacological or toxicological result
- Inactivation (usually)
- Activation (sometimes)
- No effect
- Metabolite and parent drug may both be active
Sites of drug biotransformation (5):
- Liver
- GI
- Kidney
- Respiratory tissues: lung, nose
- Brain, skin, heart
Common phases of drug metabolism: (2)
Note: don’t necessarily have to go through both phases.
- non-conjugative, (non-synthetic )
- Oxidations
- Reductions, Hydrolyses
Note: Adds or unmasks functional group
Usually inactivates, sometimes activates
- conjugative (synthetic)
- Conjugations (covalent coupling of drug to endogenous molecule)
- Increases polarity
- Adds bulky moiety
- Usually inactivating
What is this?
- “microsomal” endoplasmic reticulum mixed-function oxidase
- uses NADPH and O2 to metabolize drugs
Cytochrome P450s
The major human cytochrome P450s involved in clinical drug metabolism: (4)
CYP 3 A 4
2 D 6
1 A 2
2 C
Conjugation (Phase II) reactions pathway involves: (2)
- Need high-energy cosubstrate
- Activities reduced when low ATP
- Adds polar or ionizable group, increasing water solubility
In phase II reactions, what is the most common conjugation reaction?
- Has many enzymes and conjugates to many functional groups
- Are often excreted in the bile
glucuronides
during glucuronidation
KNOW:
Other conjugation reactions: (4)
GASM
Acetylation
Sulfation
Methylation
Glutathione conjugation
Which conjugation reaction’s main purpose is:
- to protect cells from reactive drugs and metabolites
- is not usually a major pathway for drug elimination from the plasma
glutathione conjugation
responsible for actetominophen poisoning for example
Factors affecting drug metabolism: (2)
- Increased therapeutic/ toxic effect due to reduced metabolism
- neonates, liver disease, genetics, diet, herbal preparations
- Decreased therapeutic effect due to increased metabolism
- Gene amplification
P450 modifiers in natural products: (2)
grapefruit juice
St. John’s Wort
In pharmacogenetics, genes can respond to drugs: (2)
monomorphic
polymorphic (increased plasma concentration/magnitude of response)
