Lecture 7 (EXAM 2) Flashcards
(25 cards)
A patient was presented with a yellow-colored sclera, and elevated levels of enzymes, what might the patient suffer from?
-Jaundice, damaged liver is not able to metabolize Bilirubin (high level of Bilirubin in the blood)
-disruption of liver cells causing exposure of liver enzymes to the blood
What do increased prothrombin, reduced plasma bicarbonate, and reduced glomerular filtration, and elevated serum creatinine indicate?
increased prothrombin: enzymes for blood clotting are reduced due to impaired liver
reduced glomerular filtration and elevated serum creatinine: kidney is affected too
What is the predominant organ that performs Biotransformation?
The liver (f.e. first pass)
Notice: other organs also perform Biotransformation
How are molecules altered during Biotransformation
Primarily by making it more water soluble to increase renal excretion
What are the two types of Biotransformations?
Phase 1: simple Oxidations
Phase 2: synthetic reactions or conjugation reaction
-> Addition of a large water-soluble molecule
What are the water-soluble groups that are added in Phase 2 reactions?
-Glucuronic acid
-GSH-Gluthanionie (3 amino acids)
-Sulfate (SO4-2)
-Methyl
-Acetyl
What does the general scheme of biotransformation look like?
-A drug undergoes Phase 1 and gets oxidized (-OH)
-the drug undergoes Phase 2, whereby a water-soluble drug is conjugated to the drug by linking to the oxygen
-Phase 2 reactions can also occur before Phase 1
What does the general scheme of biotransformation look like?
Absorption –> Metabolism –> Elimination
from Lipophilic to Hydrophilic
-A drug undergoes Phase 1 and is oxidized (-OH)
-the drug undergoes Phase 2, whereby a water-soluble drug is conjugated to the drug by linking to the oxygen
-Phase 2 reactions can also occur before Phase 1, several sequences and combinations are possible
What are the outcomes of Phase 1 Biotransformation?
-drug gets metabolized causing increased (prodrug) or decreased activity
OR
-inactive drug metabolite
-either way, the drug will be more water-soluble
Other sequences of Biotransformation?
-Drug undergoes Phase 1 modification and gets eliminated without undergoing Phase 2
-Drug gets eliminated without undergoing Phase 1 and Phase 2 Biotransformation (f.e. Metformin)
What are primary and secondary metabolites?
-After undergoing Biotransformation (f.e. Phase 1) there are fractions of metabolites -> 1 primary metabolite with the highest amount and multiple secondary metabolites
-the metabolites may have increased, or decreased activity, be TOXIC, or are deactivated
-after Phase 1 metabolism the metabolites have different fates (they can undergo Phase 1 again, Phase 2, or elimination with different efficacy changes)
if there are so many different outcomes, how can we predict the outcome of certain drugs?? f.e. how do we know that drug XY will undergo first pass,
What is the meaning of Cytochrome P450?
Cyto = inside the cell
chrome = color
P450 = absorbs light at lambda 450
What is required for CYP450 to absorb light at Lambda 450?
Carbon monoxide (CO)
How many genes code for CYP 450?
approximately 50 genes
What are the CYP450-dependent oxidation reactions?
-Aromatic hydroxylations (there is a toxic Epoxide metabolite)
-Aliphatic hydroxylations
-Epoxidation
-Oxidative dealkylation (carbon with oxygen comes off)
-N-Oxidation (nitrogen gets oxidized)
-S-Oxidation
-Deamination followed by an oxidation
-Desulfuration followed by an oxidation
-Dechlorination (toxic free radical intermediate)
What are the Cytochrome P450-independent oxidation reactions?
-Flavin monooxygenase (Ziegler’s enzyme)
-Amine oxidases
-Dehydrogenations
-Reductions
-Hydrolyses
Nomenclature of CYP450 2C 19
2C = Family
19 = gene location (chromosome)
What do CYPs contain in the middle of their structure?
-Porphyrin ring
-often contain a metal ion (Fe-ion) in the middle of the ring that is important for enzymatic activity
What is the enzyme that provides electrons for CYP450 to work?
P450 reductase providing e- for CYP450
-both work together in a cycle to metabolize drugs
What is the state of Fe in the porphyrin ring in the first step of the cycle?
Oxidized state: Fe3+ (ferric)
What happens to Fe in the second step?
Reduction to Fe2+ (ferrous) by the electron provided from P450 reductase
Where does the P450 reductase get its electron from?
-from NADPH which reduces a portion of the P450 reductase
-the P450 reductase will carry over the e- to the Fe3+ in CYP450
Step 3 of the CYP450 cycle
-P450 reductase donates another e-
-CYP450 carries two e- -> the 2nd electron attracts molecular O2
-O2 binds to the enzyme complex = CYP450 with Fe2+ and the bound drug
–> unstable complex
What happens to the unstable CYP45-drug complex?
-The drug will accept one oxygen
RH (drug) –> ROH
-the other oxygen will attract available H atoms and will form H2O
-the oxidized drug (ROH) is not metabolized and loses affinity to the complex and dissociates
