Biotransformation Flashcards
What is Biotransformation?
Substance is changed from 1 chemical to another
Biotransformation usually takes xenobiotics to more ____ compounds that are ____ in size
More polar
Larger in size
Main location for Biotransformation?
Liver
- can also occur in GI, lungs, skin, kidneys
Describe the 1st pass effect
- Oral drugs absorbed in small intestine
- Transported in hepatic portal system
- Reach the liver and undergo metabolism
= LIMITS AVAILABILITY
The 1st pass effect limits?
Availability of a drug due to its metabolism in the liver
What is an example of a drug that is given via another route due to the 1st pass effect?
Morphine
Main purpose of Phase 1 of Biotransformation?
Inactivate drug and break it down
Catabolic phase of Biotransformation
Phase 1 (break down)
What methods are usually involved with Phase 1 of Biotransformation?
Oxidation
Reduction
Hydrolysis
End product of Phase 1 of Biotransformation?
More polar and More reactive
What enzymes carry out Phase 1 of Biotransformation?
Mixed function oxidases
ex. CYP450 (CYP3A4)
Where are the enzymes located for Phase 1 of Biotransformation?
ER membranes of liver
Main purpose of Phase 2 of Biotransformation?
Increase water solubility and molecular weight in order to excrete it
Anabolic phase of Biotransformation
Phase 2 (build)
What carries out Phase 2 of Biotransformation?
Endogenous substances
Endogenous substances form a ____ of the substrate in Phase 2 of Biotransformation
Conjugate
Which Phase in Biotransformation is faster?
Phase 2
What is Enzyme Induction?
Dissimilar xenobiotics induce P450s by enhancing rate of enzyme synthesis or slowing rate of enzyme degradation
Enzyme Induction ______ substrate metabolism
INCREASES
Enzyme Induction _____ substrate effects
DECREASES
What is Enzyme Inhibition?
Interaction between drug and enzyme that leaves biotransformation enzyme inhibited
Enzyme Inhibition _____ substrate metabolism
DECREASES
Enzyme Inhibition ____ substrate effects
INCREASES
Can enzyme inhibition be reversible or irreversible?
Both
In neonates, why are they susceptible to drug toxicity?
LOW hepatic enzyme activity involved with biotransformation
In the elderly, what diseases could make them more susceptible to drug toxicity?
Liver and kidney disease that cause decreased metabolism
What processes help convert Acetomenophin into non-toxic substrates?
Glucuronidation and GSH conjugation
Sulfation
If the endogenous substances used in glucuronidation and sulfation of Acetomenophin are depleted, what will occur?
Toxic metabolites build up = LIVER CELL DEATH
When GSH is depleted faster than it is regenerated, what occurs?
Liver cell death due to toxic metabolites from Acetomenophin
Pharmacogenomics
Study of the entire genome to assess drug response
Pharmacogenetics
Study of differences in drug response due to allelic variation in genes
Allele
Alternative form of a gene
Polymorphism
Variation in DNA sequence that is present in more than 1% of the population
Single Nucleotide Polymorphism (SNP)
Base pair substitution
2 Phase 1 enzymes that contribute to variability in drug response?
CYP2D6 - cannot convert Codeine to Morphine
CYP2C19
2 Phase 2 enzymes that contribute to variability in drug response?
UGT1A1
TPMT
Normally, what does G6PD produce?
NADPH that then regenerates reduced Glutathione
NADPH regenerates reduced Glutathione. What does that do?
Protects cells against oxidative damage
Those with variations in G6PD have what?
Abnormal RBC destruction in presence of oxidants due to decreased NADPH and reduced Glutathione
2 genes are known to capable of variations when it comes to therapy with Warfarin. What are those genes?
VKORC1 - increased risk for excessive anticoagulation after warfarin
CYP2C9 - increased risk for bleeding due to decreased clearance of S-warfarin
4 steps to getting a drug on the market?
In vitro
Animal studies
Clinical Trials
Marketing
What is a lead compound?
Starting point in a drug for modifications to improve parameters
(in vitro)
When do you submit an IND (investigational new drug)?
After animal testing and Before clinical trials
Clinical Trials have 4 phases. Describe Phase 1.
20-100 patients
Is it safe?
Clinical Trials have 4 phases. Describe Phase 2.
100-200 patients
Does it work?
Clinical Trials have 4 phases. Describe Phase 3.
1000 -6000 patients
Does it work double blind?
Clinical Trials have 4 phases. Describe Phase 4.
Post-marketing surveillance
When do you submit an NDA (New Drug Application)?
After clinical trials and before marketing
Purpose of IRB (institutional review board)?
Protects rights, safety and welfare of humans participating in the clinical trials
- can approve/disprove or require modifications to research
Established therapy against which the new agent can be compared
Control
Patients entering the trial have an equal probability of receiving the test or control agent
Randomized
Neither the health professionals nor the patient know whether the patient is receiving the experimental or control agent
Double blind
The health professionals, but not the patient, know which treatment the patient is getting
Single blind
Both health professionals and patients know whether the drug is the experimental or control agent
Open label
At least 2 regimens are tested simultaneously, but patients are assigned to only 1 therapy
Parallel trial
Patients receive each therapy in sequence and therefore serve as their own controls (i.e. A before B or B before A)
Crossover trial
Measured to assess a drug’s effect
Endpoint
An outcome of therapy that predicts the real goal of therapy without being that goal (i.e. reduction in tumor size as a surrogate for survival)
Surrogate endpoint
