EXAM 5 - Biochemical variables that affect drug/xenobiotic metabolism Flashcards
Explain the following graph.
The graph shows the reaction velocity (how fast the enzyme is working) depending on the concentration of substrate available.
Explain the relation between reaction velocity and substrate concentration for alcohol dehydrogenase at 0.1% BAL, if the Km for ethanol is 50uM to 4mM, and at 0.1% BAL = 22mM.
This means at 0.1% BAL, ADH enzymes are saturated and additional ethanol goes directly into the blood.
Describe metabolism when [chemical] > Km.
When the concentration of the chemical is much greater than the Km:
* fully saturated
* zero-order kinetics (the velocity is no longer dependent on the substrate concentration [S]
* metabolism rate = Vmax
Describe metabolism when [chemical] = Km.
When the concentration of chemicals is equal to Km:
* the reaction velocity is responsive to changes in substrate concentration
* similar to first-order kinetics
* metabolism rate = Vmax/2
Describe metabolism when [chemical] < Km.
- very responsive to changes in chemical concentration
- true first order kinetics
Explain why metabolic enzymes are expressed in some tisesues and not others and are in specific locations within the cell.
Tissue specificity - because of tissue specific promoters
* only certain tissues have the promoters necessary for the enzyme to be expressed.
Subcellular location - subcellular specific targeting signals on proteins
* direct enzymes to specific locations within the cell.
What is true about the half-life of most metabolic enzymes?
Most metabolic enyzmes are constituitively (continuously) expressed.
* regardless of the concentration of cells.
What is true about the half-life of most metabolic enzymes?
Most metabolic enyzmes are constituitively (continuously) expressed.
* regardless of the concentration of cells.
List some biological and physiological factors affecting xenobiotic metabolism.
- diet
- hormones
- age
- genetics
- disease
Explain how development and aging impacts drug metabolism.
In general, metabolic enzymes are low/absent in the fetus and neonate, develop rapidly after birth, are the highest in early adulthood, and decline as adults age.
* before birth, the metabolic capacity is low bc maternal metabolism provides this
* after birth, many P450s and some phase 2 enzymes (UGTs) are expressed to eliminate bilirubin and protect against jaundice
* Milk feeding and puberty are associated with metabolic enzyme expression
In general, what is the difference between the half-lives of drugs in neonates and adults?
Neonates have a longer half-lives than adults.
* this is because they have little metabolic enzymes
Describe the differences in xenobiotic metabolism between genders.
The differences in metabolism between males and females are small.
* genetic and environmental factors play a more important role
* however, rats have marked variation between males and females
Describe the differences in xenobiotic metabolism between genders.
The differences in metabolism between males and females are small.
* genetic and environmental factors play a more important role
* however, rates have marked variation between males and females
Describe the effects of hormones on xenobiotic metabolism.
Pituitary hormones, growth hormone, thyroid hormones, and steroid hormones can alter xenobiotic metabolism.
* hormone effects are not directly related to gender differences.
Describe the effects of pregnancy on xenobiotic metabolism.
Pregnancy is associated with altered hormone levels
* progestrone
* placental hormones
Describe the effects of mutant genes within drug metabolism genotypes.
wt/wt - 75% therapeutic effect and 1% toxicity
wt/m - 85% therapeutic effect and <10% toxicity
m/m - 95% therapeutic effect and >80% toxicity
Explain the result of a deleted metabolic gene.
deleted gene –> no enzyme expressed –> no metabolism
* P450s involved: CYP2D6*4, 5 & CYP2C192, *3
Explain the result of a single metabolic gene.
4 possibilities:
1. no enzyme expressed –> no metabolism
2. unstable enzyme produced –> reduced metabolism
3. normal enzyme –> normal metabolism
4. altered substrate specificity –> other metabolites possibly formed
CYP2D6 involved for all possible outcomes
Explain the result of duplicated or multiduplicated metabolic genes.
Duplicated genes –> higher enzyme levels –> increased metabolism –> no therapeutic effect bc the drug is metabolized before therapeutic effect is reached
Involves CYP2D6
Explain the function of TPMT.
TPMT is used to metabolize drugs called thiopurines.
* thiopurines suppress the body’s immune system –> kills cancer cells
TPMT regulates thiopurines so that they metabolize at a rate that doesn’t kill other cells –> determines dosing regimen
What are the possible effects of different TPMT alleles in humans?
There are 4 possible TPMT alleles
* alleles 2, 3A, and 3C cause TPMT deficiency –> decrease TPMT functionality
What happens when TPMT deficient patients are given normal dose?
Increased systemic exposure to anticancer/thiopurines and increased toxicity because they cannot metabolize thiopurines properly.
* these patients will have increased adverse effects
Explain how we can determine if a patient is TPMT deficient.
Genotyping –> we can see if they have mutant alleles present
* based on genotyping we can “individualize” their dose for ideal therapeutic results.
