Unit 1. Lec 3- Pharmacokinetics III Flashcards
What is the main phase II reaction?
Conjugation (via transferases)
What are the main mechanism of conjugation reactions?
- Coupling of the drug
- Polar metabolite from phase I rxn uses enzymes known as transferases to an endogenous substrate
List the types (6) of conjugation reactions
- Sulfatation
- Actetylation
- Methylation
- Glucoronidation
- GSH (reduced glutathione)
- Amino acids (e.g. glycine)
Mechanism of Glucoronidation
Conjugation rxn
Covalent addition of glucaronic acid (e.g. morphine)
Mechanism of Sulfatation
Conjugation rxn
Addition of sulfate group (e.g. minoxidil)
Mechanism of Acetylation
Conjugation rxn
Addition of acetyl group (e.g. sulfonamide antibotics)
Mechanism of Methylation
Conjugation rxn
Addition of Methyl group
Mechanism of GSH (reduced gutathione)
Conjugation rxn
Addition of glutathione
Mechanism of amino acids
Conjugation rxn
Addition of amino acids (e.g glycine)
Why are most conjugates highly polar?
- It makes them water soluble and unable to cross the plasma membrane
- Making them almost always pharmacologically inactive and of little or no toxicity
List factors (7) that influence drug metabolism
- Physiologic or disease state
- Genetic Variation
- Drug Dosage
- Age
- Route of Drug Administration
- Enzyme Induction
- Enyzme Inhibition
What can influence a drug’s hepatic clearance?
Pathological factors that alter liver function
How can congestive heart failure (inefficient pumping) affect drug metabolism?
It can decrease hepatic blood flow and distribution of drugs
What can alter the ratio of bound to unbound drug?
Alteration in albumin production
What is the main site of serum-albumin production and drug biotransformation?
Liver
Explain how genetic variation can influence drug metabolism.
- There is a great variation in the activity of N-acetyl transferase enzyme among different population.
- The proportion of drugs metabolized by the major cytochrome P450 enzyme (know about CP450 CYP2D6 is a polymorphic drug-metabolizing enzyme)
If you are a fast acetylator, do you have more or less drug concentration in blood? Do you have more or less tranferase?
Less drug [ ], More transferases
If you are a slow acetylator, do you have more or less drug concentration in blood? Do you have more or less tranferase?
More drug [ ], less transferases
How does dosage influence drug metabolism?
- As drug dosage increases = drug [ ] may saturate metabolic enzyme
- If Phase II enzymes are saturated, it gets metabolized by CYP450 enzymes
- This can lead to an Intermediate that causes Hepatic cell death
ex: high dosage of acetaminophen causing hepatic cell death
How does age influence drug metabolism?
- Young children: (primarily infants) Drugs may be MORE ACTIVE, b/c lack of development of Phase I & II enzymes (No enzymes=NO biotransformation)
- Older childen: Drugs may be LESS active than in adults if the drug is given based on weight. Liver develops faster than the general increase in body weight
- Older people: metabolizing enzymes decline
How does the route of drug adminstration influence drug metabolism?
- If drug is taken orally the first pass effect influences how the drug is metabolized
- First pass effect: Combined action of bacterial enzyme within intestine and liver on the drug taken orally.
How does enzyme induction influence drug metabolism?
- Increases the synthesis or decreases the degrading of certain drug metabolizing enzymes
Increases enzyme that breaks drug down
E.g. Cigarette smokers have a polycyclic aromatic hydrocarbon component that induce the N-demethylation (Phase I) pathway
What two drugs act as Enzyme Inducers?
- Phenobarbital
- Rifampin
Enzyme induction can produce a condition known as ____
Pharmacokinetic Tolerance:drugs can block certain enzymes that are involved in metabolizing other drugs
