Chapter 4 lecture 5-6 Flashcards
Give another definition of toxicokinetics
- The time-course of movement of chemicals through the body
- how does the body dispose of a xenobiotic
What does the severity of toxicity depend on?
its concentration at the site
of action.
Recall what ADME are
- Absorption: How do toxicant enter to our body?
- Distribution: Whether the absorbed compound could move from the site of entry to the target organ to elicit toxic reaction
- Metabolism: Whether the chemical could be metabolized to a more or less toxic compound
- Excretion: How and how rapidly the chemical is removed from the body
What are the 7 aspects that are important for toxic disposition?
- Duration and concentration of substance at the site of entry
- Rate and amount that can be absorbed
- Distribution in the body and concentration at specific body sites
- Efficiency of biotransformation and nature of the metabolites
- The ability of the substance or it’s metabolites to pass through cell membranes and contact with specific cell components (e.g., DNA).
- The amount and duration of storage of the substance (or it’s metabolites) in body tissues
- The rate and sites of excretion
ADME are interelated, T/F?
True
What is the precise definition of absorption?
the process whereby toxicants cross body
membranes and enter the bloodstream
if the ingested material has not passed the ceullular barriers, should it be considered inside the body?
No, must pass through cellular barriers
What does route of absorption describe?
different pathway which chemical enters to our body
What does amount of absorption describe?
The amount of chemical absorbed determine how much it reaches the site of action
How is cell membrane related to absorption?
- formidable barriers
- a major body defense that prevents foreign invaders or substances from entering body tissues.
- cells are so tightly that can barely be pass through
What is the basic requirement for xenobiotics to cause adverse effects?
Must be able to penetrate multiple cell membranes.
Why many toxicants are hydrophobic?
The phospholipid bilayers of cell mem is hydrophobic.
What are the physiochemical characteristics of the substance that determine absorption?
- Size/shape
- Lipid solubility/ hydrophobicity
- Structural similarity to endogenous molecules
- Charge/ polarity
Bisphenol A (BPA) an endocrine disruptor. Structure similar to estrogen
Name some features of passive diffusion
- Along concentration gradient
- Diffusion will continue until the concentration is equal on both sides of the membrane
- Substances with high lipid solubility can move either through small pores or directly through membrane
- Non-polar/ionized substance
- Small hydrophilic molecules can pass through channel proteins
Name some features of facilitated diffusion
- Does not require energy
- carrier-mediated
- Move larger molecules
- transport of sugar and amino acids
- Process is saturated and competitively inhibited
Passive diffusion vs Facilitated diffusion
- Passive diffusion:
-no limit to the number that can fit through the membrane
-rate of diffusion increases linearly when more particles at one side of the membrane. - Facilitated diffusion:
-the rate of diffusion is determined by the number of channels and number of particles
Both do not require ATP
Name some features of active transport
- Transport xenobiotics into liver, kidney and CNS
- Electrolyte and nutrient balance
- Specific membrane carrier -> low to high conc
- Needs metabolic energy -> ATP
- Can be inhibited by metabolic poison
- May be saturated at high conc/ compete for uptake
Name some features of endocytosis
- invagination of membrane (vagin jeng)
- Can absorb large materials
- Against conc gradient
- Phagocytosis (cell eating): large particles in extracellular fluid, transported into cells or are destroyed within the cell
- Pinocytosis (cell drinking): engulfing of liquids or very small particles in extracellular fluid
Describe what is distribution
the process whereby an absorbed chemical moves away from the site of absorption to other areas of the body.
After passing through the cell lining, where will the chemical pass though?
Interstitual fluid of the organ
What are the 3 types of body fluid?
- Intracellular fluid
- Interstitual fluid
- Blood plasma
1 and 2 slow moving
3 fast moving
How can toxicants leave interstitual fluid?
- entering local tissue cells
- entering blood capillaries
- entering lymphatic system
Distribution does not require the penetration of membranes, T/F?
False
What does plasma level reflect?
- The conc of chemical in tissue
- Conc of chemical at the target site
- Used to calc half-life, volume of distribution, body burden etc.
How to calculate volume of distribution?
Vd = Dose/Plasma conc
Units in (L)
What is the meaning of Vd?
The total volume of body fluids in which a toxicant is distributed.
How extensive the toxicant is distributed
How to calculate body burden?
Body burden = plasma conc x Vd
Can body burden be possible to predict the amount of chemical remaining in the body?
in the body at any time
Yes
What does low or high Vd stand for?
Low Vd: Confine to plasma, not to tissue
High Vd: Localize/binds to tissue
Describe the interaction of xenobiotics with plasma protein
The distribution of a xenobiotic is greatly affected by
whether it binds to plasma protein.
only the free substance is available to pass through the capillary membranes.
greatly affects distribution, prolongs the
half-life within the body, and affects the dose threshold for toxicity.
greatly affects distribution, prolongs the
half-life within the body, and affects the dose threshold for
toxicity.
the degree of biotransformation, storage, and elimination (and thus toxicity) can be influenced by the time course and path taken by the chemical as it moves through the body. T/F?
TRUE
The route of exposure is very influential
Give some examples of toxicant distribution in our body
- Toxicants absorbed in GI tract will be carried bt the blood to liver by portal system.
- Toxicants that are absorbed through the lung or skin enter the blood and go directly to the heart and systemic circulation. WILL PASS THROUGH OTHER ORGANS BEFORE REACHING LIVER
- A toxicant that enters the lymph of the intestinal tract will not go to the liver first but will slowly enter the systemic circulation.
What will lipophilic toxicants be metabolized to?
Usually hydrophylic metabolites, where lipophilic toxicants are hard to be eliminated
What can metabolism do to toxicants?
- Decrease the toxicity of the chemical (detoxification)
- Increase the toxicity of the chemical (bioactivation)
- Producing toxic intermediates to damage tissue
What ar ethe 2 pathways of metabolism?
Phase 1: reactions which modify thechemical by** adding a reactive chemical structure**. (allows the substance to fit Phase II enzymes)
Phase II: enzymatic reactions that conjugate the modified xenobiotic with another substance. (Larger molecule, pollar, water soluble, so that they can be excreted)
What is the exception of metabolism pathway?
- the xenobiotic already has a functional group that can be conjugated
- biotransformed by a Phase II reaction without Phase I reaction.
What are the 3 main Phase I reactions?
Oxydation, reduction, hydrolysis
REDOX, Hydrolysis
What is hydrolysis?
The adiition of water splits the toxicant into 2 or smaller molecules. OH- incorporate one, H+ incoporate another.
What are the phase II reactions?
- Conjugation reactions with our body molecule
- Phase II metabolite is hydrophlic, readily eliminated
What are the 2 examples of Phase II reactions?
- glucuronide conjugation
- sulfate conjugation
Elimination from body is crucial in determining the
potential toxicity of a xenobiotic. T/F?
TRUE
What substance has advantage to be eliminated first?
Polar substances>lipid-soluble substance
What are the major routes of excretion?
- Urine (Urinary system)
- Feces (GI system)
- Exhaled air (Respiratory system)
