metabolism Flashcards
drug metabolism definition
Any chemical change made to the drug by the body
a.k.a. biotransformation
parent drug > metabolite
are most drugs metabolized? what are the main outcomes?
Most drugs are metabolized to some extent
Main outcomes:
1) Drug becomes more water soluble
> better renal excretion
2) drug may be inactivated
what is a prodrug?
A prodrug is an inactive drug that must be metabolized to its active form – e.g., enalapril (inactive prodrug) is metabolized into enalaprilat (active metabolite)
what organ filters all drugs to some extent? what drugs are more easily exctreted and why?
All drugs are filtered to some extent by the kidneys
Lipid-soluble drugs are not readily excreted because they can easily diffuse out of the renal tubule through membranes
>most water soluble drugs are excreted
locations of drug metabolism: main and less common sites
Locations of drug metabolism Mainly LIVER
Less common sites:
* Gut (microbes, enzymes)
* Lung
* Skin
* Kidneys
* Brain
* Blood plasma
two main types of metabolic reactions
- Phase I: Non-synthetic “functionalization”
- Phase II: Biosynthetic “conjugation” reactions
what is phase I drug metabolism? what does it do and how does it work? how is it mainly acheived?
Phase I metabolism (Non-synthetic reactions)
Inactivate drug by creating or uncovering reactive groups
such as:
-OH, -COOH, -NH2, -SH
Achieved mainly via oxidation
(Reduction and hydrolysis reactions are also important)
what properties do phase I metabolites have that are often different from their parent molecule?
Phase I metabolites are usually more water-soluble than the parent molecule and usually more chemically reactive
What are the names of some phase I metabolic enzymes? where are they found?
- Mixed function oxidases (MFOs)
- P450 / cytochrome P450 / CYP / CYP450 enzymes
- Microsomal enzymes
- They are found in hepatic ER membranes
what are the general characteristics of a phase I metabolite?
Pharmacologically inactive (usually, but not always)
Often more chemically reactive
More water-soluble
> if filtered, more likely to remain in urine
what is the mechanism of phase II drug metabolism? what does it produce and where? what properties do the products have?
Phase II metabolism (Synthetic or conjugation reactions)
Attach drug molecule (or Phase I metabolite) to a substance from the diet
> produces drug “conjugates”
> usually polar, inactive, readily excreted
> conjugation enzymes are located in the cytoplasm
what type of enzymes do phase II metabolic reactions use? What dietary components do they use?
Involves transferase enzymes Uses dietary components such as:
* Glucuronic acid
* Glutathione
* Acetic acid
* Sulfate
* Amino acids
why are some species worse at phase II drug metabolism? What species, and what are the consequences?
Some species (cats!) are deficient in conjugating enzymes (glucuronidation occurs but is slow)
> drugs have longer duration of action & achieve higher concentrations
Cats are deficient in certain transferases
> have difficulty metabolizing many drugs
what is the metabolic process of acetaminophen? When do we see an overdose? What is a major consequence of this? what alternative metabolic pathway can help, and how can we use this to our advantage??
Normally, only a tiny amount of acetaminophen undergoes Phase I metabolism
The vast majority is simply conjugated either to glucuronic acid or sulfate - harmless acetaminophen conjugates
An overdose of acetaminophen overwhelms conjugation pathways; excess drug is oxidized by P450 (CYP) enzymes into a highly reactive (toxic) intermediate metabolite (NAPQI) that damages every macromolecule it contacts (cell necrosis!)
> liver failure may occur if dose is high enough
Glutathione conjugation can inactivate the tiny amounts of this reactive intermediate that are normally produced, but in overdose situations glutathione stores are depleted
> administer a source of glutathione (n-acetylcysteine)
> minimizes hepatic damage
what are the possible routes of drug metablism?
Drug
> phase I
> drug metabolite with modified activity
> phase II
> conjugate (usually inactive)
> phase I
inactive drug metabolite
phase II
conjugate (usually inactive)
> phase I
polar drug metabolite
elimination
> phase II
conjugate (usually inactive)
> Drug directly eliminated
> phase I
active drug metabolite
elimination, or
phase II
conjugate (usually inactive)
> phase I
inactive drug metabolite
phase II
conjugate (usually inactive)
back to phase I, inactive drug metabolite
elimination
