Module 1 Flashcards
What three properties of the xenobiotic affect its ability to be absorbed?
Lipophilicity, pH and size
What is the coefficient used to measure lipophilicity in chemicals?
octanol:water partition coefficient, log Kow
What does a low Kow value represent?
A low Kow means the molecule is very lipophilic and can easily diffuse out of blood and has a high potential for accumulation and toxicity
What is an example of a class of xenobiotics that have a low Kow constant?
organochlorine pesticides. e.x. DDT
How does pH affect the xenobiotics ability to be absorbed?
Only non ionized form of xenobiotics can passively diffuse across cell membranes, nonionized form of acids are protonated, nonionized form of bases are unprotonated
What is the equation to determine the ratio of nonionized vs ionized xenobiotics in the body?
pKa - pH = log ([p+]/[non-p+])
What would happen if you had a weak base drug in an acidic environment?
The xenobiotic would become ionized and not be able to leave the target site, could be good for sites of infection, aka mastitis, or could lead to increase toxicity, e.x. fetal blood pH
What would happen if you had a weak acid in a low pH environment?
The weaker the acid, (aka higher pH) the more preferentially the xenobiotic will be absorbed
What are the four ways a xenobiotic can be absorbed into tissues?
passive transport, filtration, facilitated diffusion and active transport
Where does filtration mainly occur and why?
the glomerulus because it has gaps of 70nm while a cells is normally 2nm
What types of receptors are used for facilitated diffusion?
OATs and OCTs
What is the class of proteins that are used in active transport systems?
ATP-binding cassette proteins
How can the presence of ABCs contribute to the potential of toxicity?
They are known as lipophilic vacuum cleaners, expressed in brain, liver and kidney
What are the four main factors influencing distribution?
Perfusion, properties of the xenobiotic, plasma proteins and barriers to distribution
Why are plasma proteins important for the distribution of xeno?
only free xenobiotics can freely diffuse into tissues, and xenobiotics have differing affinities for proteins
What are some examples where certain tissues have differing binding capabilities?
Liver and kidney have high binding capacity, fat binds more and bone cam bind certain xenobiotics like lead
What are the two main barriers to distribution?
BBB and placenta
What is so important abt the BBB?
has ABCs and tight junctions so no xeno should be able to pass, but in birth its not fully developed
What is important abt the placental barrier?
xeno can cross placenta
What is the equation for Vd?
Vd= total xenobiotic dose / [plasma xenobiotic]
What is the definition of Vd?
the apparent fluid volume in which a xenobiotic appears to be dissolved?
What does a high vs low Vd mean?
High - extensive distribution, high affinity for tissues
Low- restricted to blood plamsa, mainly due to high plasma protein binding
What is the purpose of biotransformation?
converts lipohphilic xenobiotics into highly water soluble metabolites for excretion
How does Phase 1 biotransformation work?
modify through oxidation-adds OH to group
What is the class of the most important Phase 1 enzymes?
Cytochrome P450-dependent monooxygenases
What are two adjectives used to describe CYP enzymes and what do they mean?
broad: one enzyme can biotransform many xeno
overlapping: one xeno can be transformed by many enzymes
Where are CYP enzymes normally found in the cell?
On the endoplasmic reticulum
What is an example of regular body functions where CYP enzymes are used?
In making the steroid hormones
What is an example of how CYPs can bioactivate certain metabolites?
parathion to paraoxon
What is “first pass” transformation
The almost complete inactivation of xenobiotics after given through oral ingestion
What is oral bioavailabilty?
The fraction of an orally administered drug that reaches the systemic circulation in an unchanged form
How do Phase 2 reactions occur?
Add large soluble functional group to xenobiotic to make it even more water soluble
What are the four major phase 2 pathways
glucuronidation, sulfation, acetylation and gluathione conjugation
What is the enzyme and cofactor used in glucuronidation?
UDP-glucuronosyl transferase and UDP-glucuronic acid
What is the enzyme and cofactor used in sulfation?
sulfotransferase and cofactor PAPS
What is the enzyme and cofactor used in acetylation?
N-acetyltransferase and acetyl coenzyme A
What is the enzyme and cofactor used in glutathione conjugation?
Glutathione-S-transferase and glutathione
Why is glutathione so important for our cells?
detoxify ROS and epoxides
What are the six genetic and environmental ways that bioactivation can be affected?
- Enzyme induction and inhibiton
- Intraspecific differences
- Interspecific differences
- Sex and age
- Diet
- Disease
Explain how enzyme induction and inhibition can lead to differences in bioactivation
enzymes can be induced or reduced
Explain how intraspecific differences can lead to differences in bioactivation
polymorphisms can lead to different levels of expression
Explain how interspecific differences can lead to differences in bioactivation
different expression of enzymes, e.x. cats have no UGT
Explain how sex and age can lead to differences in bioactivation
sex differences in cyp, old and young have lower enzymes
Explain how diet can lead to differences in bioactivation
enzymes can inhibit certain enzymes, e.x. grapefruit juice nd CYP3A4
Explain how disease can lead to differences in bioactivation
impaired liver can cause decreased bioactivation
How does tubular secretion play an important role in xenobiotic excretion?
OATs and OCTs are present in the tubules as many xenobiotics are - charged so they can be excreted
How does glomelular filtration play an important role in excretion?
for nitrogenous wastes, and as some proteins (like albumin) cannot pass through
How does tubular reabsorption play an important role in excretion?
proximal tubule plays a very important role, pH is slightly more acidic so acids will diffuse back into the blood and water leaves at this point so it must be very hydrophilic or else it won’t leave bloodstream
How does biliary excretion work?
larger molecules (>300g MW) use OATS to get into hepatocytes and then ABCs to get into bile ducts
What is enterohepatic cycling?
Xenobiotics excreted in the bile can be reabsorbed and distributed back into the liver, exacerbating liver toxicity
What are 5 other methods of excretion?
Pulmonary, lactation, saliva, sweat, keratin
What are the four interactions of xenobiotics?
Summation, synergism, potentiation and antagonism
What is summation?
there is no interaction of the xenobiotics but the effects are additive
What is synergism?
the effects of 2 xenobiotics in combination exceeds the sum of their individual effects
What is potentiation?
a xenobiotic with no effect intensifies the effect of a second xenobiotic
What is anatgonism?
the effect of 2 xenobiotics in combination is less than the additive
What does the slope of kel look like in the one compartment model
negative linear
What does the graph look like for the two compartment model?
A steeper linear slope in the beginning and then another less steep linear line connecting it
What do the two slopes represent in the two compartment model?
alpha is the slope of the distribution phase, and beta is the elimination rate
What does a first order kinetic graph look like?
Negative curved graph, proportional to Cp
What does a zero order kinetic graph look like?
negative linear slope, constant elimination
After how many half lives is steady state achieved?
4 half lives
What is bioaccumulation?
the net accumulation of a xenobiotic in an organism from all exposure routes, commonly occurs with highly lipophilic contaminants
What is bioconcentration?
specific case where net accumulation of a xenobiotic in an organism is from water only
What is the bioconcentration factor?
BCF = [xenobiotic in organism] / [xenobiotic in water]
What is biomagnification?
occurs when xenobiotic concentrations increase through at least three trophic levels in a food chain, occurs with highly lipophilic xenobiotics and at least 10x in concentration
