Metabolism Flashcards
What is drug metabolism?
Metabolism is a defense mechanism against adverse effects of lipophilic xenobiotics
What 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
• There would be a tissue drug accumulation
• Potential toxicity
What is the organ that is the main place for drug metabolism in the body? What is the name of the process?
The liver is the major organ for drug metabolism in the body
Hepatic biotransformation and biliary excretion
Drug metabolism in the liver depend on what 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
• Physicochemical properties of the drug (pKa, lipid solubility, molecular weight)
Where are most drugs eliminated?
Most drugs are eliminated by hepatic metabolism, renal excretion, or both
How are lipid soluble drugs metabolized?
Lipid-soluble drugs require conversion to a water- soluble form before they can be eliminated by the
kidney
Hepatic metabolism can be divided into ____ phases
2
What other organs have substantial metabolic capacity?
- Kidney
- Lungs
- Skin
- GIT
The kidney is also capable of ________ some drugs, although this capacity is only occasionally of ____ _____
The kidney is also capable of metabolizing some drugs, although this capacity is only occasionally of clinical importance
Where are most metabolizing enzymes located? Where is the others located?
Most metabolizing enzymes are located in the smooth endoplasmatic reticulum (SER) of the hepatocyte, others are located in the cytosol of the cell
Where can you find Cytochrome P450 enzymes (CYP450 or CYP)? What is it consisted of?
The enzymes located in the SER consist of a protein (cytochrome) with an iron central core (pigmented) that absorbs light at 450 nm when bound to carbon monoxide
What do the reactions of all CYP- mediated drug metabolism have in common??
All CYP-mediated drug metabolic reactions involve the addition of a single atom of oxygen onto the subtrate
What reactions are included on phase one of hepatic metabolism?
Oxidation: addition of oxygen across a carbon double bond, addition of oxygen to a carbon chain Loss of an electron
Hydrolysis: Splitting of the drug molecule and addition of a water molecule to each of the split portion
Reduction: Addition of hydrogen Gain of an electron
Most ______ _______ can be deactivated to inactive metabolites. In contrast, some drugs can also be activated from an inactive form, ________ to an active drug, or from an active form to an _______ ________.
Most parent drugs can be deactivated to inactive metabolites. In contrast, some drugs can also be activated from an inactive form, prodrug to an active drug, or from an active form to an active metabolite
Which species of animals have the most oxidation that occurs?
- Oxidation is higher in horses.
What is the order of oxidation capacity from largest to smallest?
Oxidation is higher in horses > cattle > dogs > cats
The duration of pentobarbital anesthesia in horses is ______ than in dogs.
Shorter
What is phase two of hepatic metabolism? What are the reactions that take place during this phase?
Phase II, also known as conjugation, occurs when a large water-soluble molecule is chemically added to either the parent drug or its phase I metabolite
• Glucuronidation is the most common phase II reaction.
Glucuronide conjugates are eliminated in the urine and
bile
• Sulfation and acetylation are also phase II reactions
What is another name for phase II of hepatic metabolism?
Conjugation
What enzymes are involved in phase 2 metabolism?
Involved enzymes : glucuronosyltransferase, sulfotransferase, N-acetyltransferase and methyltransferase
As in humans, _________ in drug-metabolizing enzymes has been reported in dogs but it is _____ ______ _____ ______.
As in humans, polymorphism in drug-metabolizing enzymes has been reported in dogs but it is not as well described
What do polymorphisms in CYP metabolic enzymes have an association with?
Polymorphisms in CYP metabolic enzymes have been associated with therapeutic failure
As a result:
• Extremely rapid metabolism of a drug
• Toxic effects caused by decreased metabolism
What is the issues greyhounds have with anesthetic agents? What are some drugs that this can be seen with?
Cytochrome-mediated clearance of anesthetic agents is less in Greyhounds compared with other (nonsight hound) dogs
Documented drugs include:
Thiopental, thiamylal and methohexital
Clearance of propofol by Greyhounds is _______ _______ _______ than by Beagles
Clearance of propofol by Greyhounds is three time less than by Beagles
What is the aspirin half life in cats? Dogs? How is toxicity prevented?
Aspirin half-life approximates 36 hours in cats compared with 8 hours in dogs. To prevent toxicity in the cat, aspirin is dosed every 48 to 72 hours, compared with twice daily in dogs
What causes cats to have acetaminophen shunted more aggressively back into phase I metabolism, and what is the outcome? What tissues are affected if this happens?
Because cats are deficient in glucuronidation, excessive acetaminophen is shunted more aggressively back into phase I metabolism, which produces toxic oxygen radicals. More metabolites are produced than can be handled causing destruction of tissues (liver and RBCs)
