Biotransformation Flashcards
Xenobiotic
A chemical found in an organism which is not normally produced or expected to be in it
4 properties of pharmacokinetics
Absorption, Distribution, Metabolism, Excretion
What crosses membranes more readily, polar molecules or non-polar molecules?
Non-polar molecules
What types of molecules tend to get filtered at the glomerulus?
Small, charged, non-protein bound molecules
Where do most metabolic enzymes in the liver appear and what are these enzymes called?
In the membranes of the smooth ER (also a little bit in microsomal fraction of tissue homogenate and thus are called microsomal enzymes)
What is the underlying purpose of drug metabolism?
To make less polar drugs into more polar drugs so that they can be eliminated via the kidneys
What type of compounds are most readily excreted by the kidneys, hydrophilic or hydrophobic?
Hydrophilic (polar)
Phase I metabolism
Reactions to introduce or expose a functional group (typically oxidation, reduction, or hydrolysis)
Where does Phase I metabolism usually occur?
ER
What type of proteins are cytochrome p450s?
Heme-thiolate proteins
How does the activity of CYPs involved in drug metabolism tend to differ from that of CYPs involved in synthesis?
Metabolic CYPs tend to have broad specificity, synthetic CYPs tend to be very specific for substrates
Reactions catalyzed by CYP (types of chemical reactions)
Aliphatic hydroxylation, aromatic hydroxylation, N-,O-,or S-dealkylation, Oxidative deamination, dehalogenation, N- and S-oxidation
What are the most important CYP in terms of mass of enzyme and number of drugs metabolized?
3A4 and 3A5
What CYP is absent in 7% of caucasians while 33% of Ethiopians and Saudia Arabians are ultrarapid metabolizers?
2D6
Which CYP is responsible for generation of reactive acetaminophen metabolite and resultant toxicity?
2E1
Where are CYP3A enzymes located?
Liver and small intestine brush border
Fetal form of CYP which disappears soon after birth
3A7
CYP 3A enzymes interact significantly with what other biotransformation system?
P-glycoprotein (PGP)
Phase II Metabolism
Addition of a pre-formed molecule to a drugs structure (aka conjugation)
Groups added by Phase II metabolism
Glucuronic acid, sulfate, glutathione, amino acids or acetate (all highly hydrophilic)
What is the most important Phase II reaction, what enzyme carries it out, and what other functions does it serve?
Glucuronidation, UDP glucoronosyltransferases, also important in metabolism of endogenous steroids, bile acids, bilirubin
What is unique about sulfation and acetylation as Phase II metabolic reactions?
Sulfation - low capacity, Acetylation - high interindividual variability
What effect does enterohepatic recirculation have on the half life of a drug?
Extends it
What effects does CYP 3A have on pharmacokinetics and why?
Increases absorption and decreases elimination (because CYP 3A is in both gut and liver)
What is the most potent inhibitor of the CYP 3A family?
Ketoconazole (antifungal)
What is torsade des pointes, and what causes it?
A cardiac arrhytmia, caused by high doses of erythromyicn (can occur with CYP 3A inhibition)
What is the effect of Rifampin on the CYP system?
Induction (CYP2C9, CYP3A4, others)
What is the effect of chronic alcohol intake on the CYP system?
Induction of CYP2E1 (metabolizes acetaminophen)
Compare the timecourses of CYP induction and CYP inhibition
CYP induction much more gradual (requires creation of new protein)
Give an example of a drug that causes autoinduction and define the term
Autoinduction - a drug inducing its own metabolism. Carbamazepine (anticonvulsant) does this
How long does it take for drug levels to drop by 90% assuming first order kinetics?
3.3 half lives
Name a self-administered drug that follows zero order metabolism
Ethyl alcohol
Give two reasons that cirrhosis decreases first pass metabolism
1) Less working enzymes in the liver (e.g. CYPs), 2) Blood shunted directly into systemic circulation, decreasing direct portal circulation
