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 enzymes do cats have low activity of? What enzymes is approximately the same as dogs/ humans?
Cats have very low activity of CYP2D6 CYP2C, but activity of CYP2D and CYP3A approximates that of dogs CYP3A4
or humans
What animal has been found to have deficiencies in phase 2 metabolism?
What has been seen? What is the outcome of this?
Deficiencies in phase II metabolism have long been recognized in cats
Extremely low concentrations of some glucoronyl tranferases
Many drugs excreted as glucuronide conjugates in other species are characterized by a prolonged clearance and exaggerated pharmacologic responses. Toxic levels may accumulate much more quickly
What deficiencies lead to much slower elimination of phenols and aromatic acids/ amines in cats?
Deficiencies in phase I demethylation and hydroxylation as well as phase II glucuronidation lead to much slower elimination of phenols and aromatic acids and amines in the cat compared with other species
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)
Why is it that not all drugs conjugated with glucuronide are not predisposed to toxicity in the cat?
The cat is deficient only in certain families of glucuronyl transferase
• Cats can conjugate and excrete endogenous substrates such as bilirrubin, steroid hormones as
well as other species
• The degree of deficiency and potential toxicity depend on the drug substrate: level of
conjugation, wide safety margin (If accumulation occurs)
• Drugs may be sufficiently metabolized by an alternative pathway: Sulfate-conjugating system
What is an enzyme system whose deficiency in the dog is clinically relevant?
Acetylation is not a common route of elimination for xenobiotics, but it is an enzyme system whose deficiency in the canine (dog and other canine species) is clinically relevant
The antiarrhythmic _________ is acetylated in humans to an_______ _______. This acetylated metabolite is________ ________ than the parent drug. Because of this the canine dose for procainamide is considerably______ than that in humans in order to achieve an equivalent pharmacologic response
The antiarrhythmic procainamide is acetylated in humans to an active metabolite. This acetylated metabolite is more potent than the parent drug. Because of this the canine dose for procainamide is considerably higher than that in humans in order to achieve an equivalent pharmacologic response
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What factors affect hepatic drug metabolism?
Factors that can affect hepatic drug metabolism include:
• The amount and activity of drug- metabolizing enzymes
• Hepatic blood flow
• A flow-limited drug
- Species, age, nutritional status, tissue storage, health status.
How can diets affect CYP450?
Factors that can affect hepatic drug metabolism include:
• The amount and activity of drug- metabolizing enzymes
• Hepatic blood flow
• A flow-limited drug
• The level of oxidative enzymes is ______ ____ _____ ______ ______ . Liver enzymes systems are not fully developed until _____ ______ of age
• The level of oxidative enzymes is lower in very young animals. Liver enzymes systems are not fully developed until 3 months of age
When may the ability to synthesize liver enzymes be impaired?
The ability to synthetize liver enzymes may be impaired in old animals thus decrease the capacity to metabolize
What can inhibit the CYP450s?
• Many liver diseases such as hepatitis, liver cirrhosis and cancer inhibit the CYP450s
How can hyperthyroidism affect drug metabolism?
• Hyperthyroidism may increase the rate of metabolism of drugs while hypothyroidism
does the opposite
Why is it important for animals to get enough nourishment in regards to their ability to metabolize drugs?
Malnourished animals cannot synthesize enough liver enzymes needed for metabolism
What is important to remember when using multiple drugs that are metabolized by the liver?
When administering a drug metabolized by the liver, it is wise to anticipate a drug interaction if a second drug also metabolized by the liver is added to therapy
What is the benefit of induction of drug metabolizing enzymes?
Induction of drug-metabolizing enzymes should be considered as a protective mechanism that
facilitates excretion of potencially toxic compounds
Inducers generally act as _________ for the induced enzymes and the induction is ______ _______
Inducers generally act as substrates for the induced enzymes and the induction is dose dependent
Inducers often induce _____ ______ _____ _____
Inducers often induce more than one CYP
How long does maximal induction require for most drugs? When can it return to baseline?
Maximal induction generally requires 10 to 12 hours of exposure to a drug. It can return to baseline 18 to 24 hours (depending on dose) after the inducer is discontinued
What are recognized as inducers of CYP? What is one of the most potent microsomal enzyme inducer? What is its effect on other drugs?
Barbiturates are recognized inducers of CYP. Phenobarbital is one of the most potent microsomal enzyme inducers known and can enhance the hepatotoxicity of other hepatotoxic drugs
What is the risk with drug interactions that reflect inhibition of enzymes?
Drug interactions that reflect inhibition of enzymes may be at greater risk of causing serious adverse events
What is the extent of inhibition dependent on?
• As with inducers, the extent of inhibition is dose dependent
What do inhibitors act as at the inhibited enzyme?
Inhibitors often act as substrates at the inhibited enzyme
What are the 3 types of inhibitors?
Currently, three types of inhibitors have been described: reversible, quasireversible and irreversible
What drugs are examples of potent enzyme inhibitors?
Chloramphenicol, cimetidine and imidazole antifungal drugs are examples of potent enzyme inhibitors
What drug inhibits CYP enzymes, including CYP3A4 in dogs?
Ketoconazole
Is drug induced inhibition always bad?
Drug-induced inhibition of drug metabolism can be used for therapeutic benefit
How does ketoconazole affect drug metabolism? What is its benefit with cyclosporine?
Ketoconazole interferes with the metabolism of drugs that are metabolized via CYP3A. It has
been used to increase blood drug concentrations of cyclosporine in dogs and cats (reduce dosage/cost)
What is the benefit of using cimetidine in regards to acetaminophen ( in humans and cats)?
Cimetidine has been used to prevent metabolism of acetaminophen in humans and cats into potentially lethal toxic metabolites
What does cilastatin inhibit?
Cilastatin inhibits the metabolism of imipenem by dehydropeptidase I on the brush border of
renal tubular cells
What is the inducer and inhibitor of Omeprazole? What member of cytochrome P450 is this drug in?
Drug: Omeprazole
Inhibitor: Ketoconazole
Inducer: Carbamazepin
Member: CYP2C19
What is the inducer and inhibitor of Acetaminophen? What member of cytochrome P450 is this drug in?
Drug: Acetaminophen
Inhibitor: Cimetidine
Inducer: Insulin
Member: CYP1A2
What is the inducer and inhibitor of Cyclophosphamide? What member of cytochrome P450 is this drug in?
Drug: Cyclophosphamide
Inhibitor: Ticlopidine
Inducer: Phenobarbitol
Member: CYP2B6
What is the inducer and inhibitor of Clarithromycin ? What member of cytochrome P450 is this drug in?
Drug: Clarithromycin
Inhibitor: Cimetidine
Inducer: Barbituates
Member: CYP3A4
What is the inducer and inhibitor of Cyclosporine ? What member of cytochrome P450 is this drug in?
Drug: Cyclosporine
Inhibitor: Ketoconazole, Cimetidine, Verapamil.
Inducer: Rifampin
Member: CYP3A4
