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
Which of the following statements regarding phase I and II metabolic reactions is true?
a. Phase II acts only on phase I metabolites
b. Phase I acts on parent drugs and/or phase I metabolites
c. Phase II acts on parent drugs and/or Phase I metabolites
d. Phase II acts only on parent drugs
C
Polymorphisms in CYP metabolic enzymes have been associated with therapeutic failure. What 2 things does this cause?
- extremely rapid metabolism of a drug
- toxic effects caused by decreased metabolism
How do Greyhounds compare to other non-sighthouds in cytochrome-mediated clearance of anesthetic agents?
Greyhounds clear these drugs much slower
- 3x slower at clearing propofol compared to Beagles
Cats have low activity of CYP2C. How do they make up for this?
CYP2D and CYP3A activity approximates that of dogs or humans
Extremely low concentrations of what enzymes for Phase II of hepatic metabolism have been long recognized in cats? What does this lead to?
low concentrations of glucoronyltransferases
toxic accumulations of glucuronide conjugates
Why are phenols, aromatic acids, and amines metabolized slower in cats? How is Aspirin toxicity avoided in cats?
deficiencies in Phase I methylation and hydroxylation and Phase II glucuronidation
half-life in cats is 36 hours compared to 8 hours in dogs - cat aspirin is dosed every 48 to 72 hours compared to twice daily in dogs
How is acetaminophen metabolism affected by the glucuronidation deficiency in cats?
causes excessing acetaminophen shunting 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/RBCs)
Not all drugs that are conjugated with glucuronide are predisposed to toxicity in cats. What are 4 reasons this is true?
- cats are only deficient in certain families of glucuronyl transferases
- cats can conjugate and excrete endogenous substrates, such as bilirubin and steroid hormones
- the degree of the deficiency and potential toxicity depend on the type of drug substrate, level of conjugation, and safety margins
- drugs may be sufficiently metabolized by an alternative pathway, like sulfate-conjugating systems
What deficiency in dogs related to metabolism is clinically relevant? What are 2 examples of drug affected by this?
acetylation enzyme system deficiency
- procainamide (antiarrhythmic) - must be acetylated into a more potent active metabolite, so the canine dose is considerably higher in order to achieve a response
- sulfonamides - typically detoxified by N-acetylation, but dogs can’t rely on this pathway so they rely on alternative metabolic pathways to convert them into less active forms
What 8 things affect hepatic drug metabolism?
- amount and activity of drug-metabolizing enzymes
- hepatic blood flow
- flow-limited drug
- species
- age
- nutritional status
- tissue storage
- health status
What diets have been shown to affect drug metabolism?
flavonoids in grapefruit juice inhibit CYP3A4 in the small intestine
ginkgo biloba induced SYP219A
Why is drug metabolism slower in younger animals? Older animals?
level of oxidative enzymes is lower and liver enzyme systems are not fully developed until 3 months
ability to synthesize liver enzymes tend to be impaired in older animals
How does malnourishment affect drug metabolism? Liver diseases, like hepatitis, liver cirrhosis, or cancer? Hyperthyroidism? Hypothyroidism?
malnourished animals cannot synthesize enough liver enzymes needed for metabolism
inhibit CYP450s
increase rate of metabolism
decrease rate of metabolism
What should be anticipated if a second drug metabolized in the liver is added to a therapy protocol?
drug interactions
What is the purpose of inducing drug-metabolizing enzymes? How do inducers work?
protective mechanism that facilitates excretion of potentially toxic compounds
act as a substrate for the induced enzymes (typically more than one CYP)
What type of drugs are recognized inducers of CYP? What is the most potent microsomal enzyme inducer?
Barbiturates
Phenobarbital can enhance the hepatotoxicity of other hepatotoxic drugs (accumulation of toxic metabolites)
Why is the inhibition of drug-metabolizing enzymes typically more relevant? What does the extent of inhibition depend on?
greater risk of causing serious adverse events
dose-dependent
What 3 types of inhibitors have been described? What are 4 examples of potent enzyme inhibitors?
reversible, quasireversible, irreversible
- Chloramphenicol
- Cimetidine
- Imidazole antifungal drugs
- Ketoconazole —> inhibits CYP
What are the main 3 ways that drug-induced inhibition of drug metabolism can be used for therapeutic benefit?
- KETOCONAZOLE interferes with the metabolism of drugs typically metabolized by CYP, making it able to increase blood drug concentration of Cyclosporine in dogs and cats allowing the reduction of dosage and cost
- CIMETIDINE has been used to prevent the metabolism of Acetaminophen in humans and cats into potentially lethal toxic metabolites
- CLASTATIN inhibits the metabolism of Imipenem by dehydropeptidase I on the brush border of renal tubular cells
