Metabolism Flashcards
What is drug metabolism? What is it a defense mechanism against?
the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily
adverse effects of lipophilic xenobiotics
What 4 things would happen in biological systems without drug metabolism?
- absorbed compounds would stay in the body for a much longer period of time
- drugs would have a prolonged activity
- tissue drug accumulation
- potential toxicity
What the the major organ for drug metabolism?
liver
Drug metabolism in the liver depends on what 4 factors?
- biological properties of the liver (existence of major drug metabolism enzymes)
- hepatic volume/perfusion rate
- drug accessibility to and extraction by hepatic metabolic sites
- physiochemical properties of the drug (pKa, lipid solubility, molecular weight)
How are drugs eliminated?
hepatic metabolism, renal excretion, or both
What must happen to lipid-soluble drugs before they can be eliminated by the kidneys?
they must be converted into a water-soluble form
Other than the liver, what are 4 other organs with substantial metabolic capacity?
- kidney
- lungs
- skin
- gastrointestinal tract
Where are most metabolizing enzymes located in the hepatocytes?
in the smooth endoplasmic reticulum
What is cytochrome P450 (CYP450 or CYP)? What does it do?
a superfamiliy of enzymes located in the SER that consists of a protein (cytochrome) with an iron central core (pigmented) that absorbs light at 450 nm when bound to carbon monoxide
metabolizes drugs by adding a single atom of oxygen onto its substrate (drug)
What are the 3 reactions that can occur during Phase I of drug metabolism in the liver?
- OXIDATION: addition of oxygen across a double carbon bond or to a carbon chain, causing a loss of an electron
- HYDROLYSIS: splitting of the drug molecule and addition of a water molecule to each split portion
- REDUCTION: addition of hydrogen, causing a gain of an electron
Most parent drugs can be deactivated into ______ ______.
inactive metabolites (not destroyed!)
What is a prodrug? Active metabolite?
drug substance that is inactive must be converted into an active agent by metabolic transformation
an active form of a drug after it has been processed by the body
How does the activity of oxidative enzymes compare in different species? What does this tend to lead to?
oxidation is higher in horses > cattle > dogs > cats
duration of phenobarbital anesthesia in horses is shorted than in dogs, since there are more enzymes available to metabolize the drug
What is Phase II of hepatic metabolism known as and what happens? What is the most common reaction?
conjugation - large water-soluble molecule is chemically added to either a parent drug or its phase I metabolite
GLUCURONIDATION - glucuronide conjugates are eliminated in the urine and bile
- sulfation and acetylation can also occur
What are 4 common enzymes involved in Phase II hepatic metabolism?
- glucuronosyltransferase
- sulfotransferase
- N-acetyltransferase
- methyltransferase