Midterm 1 Flashcards
1
Q
What is the definition of toxicology?
A
Toxicology examines the adverse effects of chemicals on living organisms.
2
Q
What term is used to refer to toxic agents in the study of toxicology?
A
The term “xenobiotics” is used, which literally means “foreign chemicals.”
3
Q
What types of substances can be considered xenobiotics?
A
Xenobiotics can include industrial chemicals, pharmaceuticals (drugs), plant/animal toxins, and essentially any exogenous agent that is foreign to the body.
4
Q
Why is toxicology considered a multidisciplinary science?
A
Toxicology “borrows” approaches and techniques from many other sciences, with physiology being a primary one.
5
Q
What paradigm shift occurred in the 1970s regarding environmental contaminants?
A
The dilution paradigm was replaced by the boomerang paradigm, which recognizes that what we release into the environment can come back to affect us and other animals.
6
Q
Provide an example of a toxic chemical discussed in early lessons learned in toxicology and its impact.
A
Methylmercury in Minamata Bay, Japan, caused neurotoxicity, highlighting the severe impacts of toxic chemicals on human health.
7
Q
What significant event led to more rigorous toxicity testing of pharmaceuticals and industrial chemicals in the 1960s?
A
Disasters such as the thalidomide tragedy, which caused birth defects, prompted the need for more stringent toxicity testing.
8
Q
What advances occurred in toxicology during the 1980s and 1990s? (4)
A
Technological advances in analytical chemistry.
Increasing importance of social sciences.
Legislation to clean up contaminated sites.
Advances in molecular biology, including “omics” technologies (transcriptomics, proteomics, metabolomics).
9
Q
How is the median lethal dose (LD50) typically measured?
A
LD50 is usually measured in mg/kg of body weight.
10
Q
What is the most toxic substance ever identified?
A
Botulinum toxin.
11
Q
Who is Paracelsus, and what central concept did he identify in toxicology?
A
Paracelsus was a pioneering toxicologist who identified the central concept of the dose-response relationship, summarized by the phrase, “The dose defines the poison.”
12
Q
What are toxicokinetics, and what processes are involved?
A
Toxicokinetics refers to “what the body does to the xenobiotic” and involves the processes of absorption, distribution, metabolism, and excretion (ADME).
13
Q
What are toxicodynamics, and what do they determine?
A
Toxicodynamics refers to “what the xenobiotic does to the body” and determines the effects of the xenobiotic on cellular and physiological processes.
14
Q
What is the primary factor that allows a xenobiotic to diffuse across cell membranes?
A
The lipophilicity (lipid solubility) of a xenobiotic is the most important factor allowing it to diffuse across cell membranes. The molecular size of the xenobiotic is also important.
15
Q
What is the central compartment in the ADME process?
A
The central compartment is the bloodstream.
16
Q
What does the term “liberation” mean in the context of ADME?
A
Liberation refers to the parts of the xenobiotic that are not taken up into the bloodstream.
17
Q
What is the main route of excretion for xenobiotics?
A
The main route of excretion is renal (urine).
18
Q
What are the primary mechanisms by which chemicals cross cell membranes?
A
Passive transport
Filtration (bulk flow)
Facilitated diffusion
Active transport
Endo/exocytosis or phago/pinocytosis
19
Q
What is passive transport, and why is it significant for xenobiotics?
A
Passive transport, also known as simple or transcellular diffusion, is the most common absorption pathway for xenobiotics. It involves the xenobiotic following its concentration gradient across the membrane.
20
Q
How is the lipophilicity of chemicals measured, and what does a high log Kow value indicate?
A
The lipophilicity of chemicals is measured using the octanol:water partition coefficient (Kow). A high log Kow value (>4) indicates significant potential for accumulation and toxicity, such as in organochlorine pesticides (DDT) and “persistent organic pollutants” (POPs).
21
Q
What is the significance of weak organic acids and bases in the context of passive transport?
A
Weak organic acids and bases exist in both ionized and nonionized forms in solution. Only the nonionized form of the xenobiotic can passively diffuse across cell membranes. The relative proportion of ionized vs. nonionized forms depends on the pKa of the xenobiotic and the pH of the solution.
22
Q
What would be more preferentially absorbed from the stomach (pH = 2): a weak acid with a pKa = 3, or a weak acid with a pKa = 4?
A
Weak acid with pKa = 3:
-Log [HA]/[A-] = 3 - 2 = 1
-Antilog of 1 = 10
-Therefore, [HA]/[A-] = 10
Weak acid with pKa = 4:
-Log [HA]/[A-] = 4 - 2 = 2
-Antilog of 2 = 100
-Therefore, [HA]/[A-] = 100
Conclusion:
The weak acid with a pKa of 4 is 10 times more nonionized at pH = 2. Hence, it is more preferentially absorbed from the stomach because the nonionized form is more readily absorbed.
23
Q
An antibiotic is a weak base with a pKa of 9.5. What are the proportions of the nonionized to ionized forms of the drug in plasma (pH = 7.5) vs. breast milk (pH = 6.5)? What is the clinical relevance of this?
A
In Plasma (pH = 7.5):
-Log [BH+]/[B] = 9.5 - 7.5 = 2
-Antilog of 2 = 100
-Therefore, [BH+]/[B] = 100
In Breast Milk (pH = 6.5):
-Log [BH+]/[B] = 9.5 - 6.5 = 3
-Antilog of 3 = 1000
-Therefore, [BH+]/[B] = 1000
Conclusion:
-The drug is 10 times more ionized in the more acidic breast milk compared to plasma.
Clinical Relevance:
The concept of “ion trapping” means that as the nonionized form of the drug diffuses into breast milk, the acidic pH causes more of the drug to become ionized and thus “trapped” because the ionized form is not lipid soluble and cannot diffuse back out. This is beneficial in treating a mammary gland infection (mastitis) with an antimicrobial drug that is a weak base, as it results in an increased drug concentration at the site of infection, enhancing efficacy.
24
Q
How can the Henderson-Hasselbach equation be used to determine the ratio of nonionized to ionized forms of a xenobiotic?
A
Log (protonated / nonprotonated) = pKa − pH
It helps determine the ratio of nonionized vs. ionized forms of the xenobiotic.
25
What is the relationship between the protonated forms of weak acids and bases and their ionization?
For weak acids, the protonated form (HA) is nonionized.
For weak bases, the protonated form (BH+) is ionized.
26
Why is the nonionized form of a drug important for absorption?
Only the nonionized form of a drug can readily penetrate cell membranes.
27
At what pH does a weak acid or weak base have equal amounts of the protonated and nonprotonated forms?
The pKa of a weak acid or weak base is the pH at which there are equal amounts of the protonated and nonprotonated forms.
28
Give an example of passive diffusion of a weak acid (pKa = 4.4) from the stomach (pH = 1.4) to the bloodstream (pH = 7.4). What happens to the absorption?
In the stomach (pH = 1.4), the ratio of HA to A- is 1000:1, favoring absorption in the gut.
Once absorbed into the bloodstream (pH = 7.4), the equilibrium shifts, resulting in a different proportion of ionized to nonionized forms.
29
Explain the phrase "Like is nonionized in like" with examples.
A weak acid is more nonionized in an acidic solution (e.g., benzoic acid in a pH < 4).
A weak base is more nonionized in a basic solution (e.g., aniline in a pH > 5)
30
What is filtration (bulk flow), and what determines its effectiveness?
Filtration involves xenobiotics moving with water through gap junctions between cells due to a pressure gradient. The size of the xenobiotic is the most important factor.
31
Explain the role of facilitated diffusion in xenobiotic transport.
Facilitated diffusion is important for nutrients and electrolytes. Certain xenobiotics can compete for these systems, mimicking endogenous molecules. Major families include organic anion transporters (OATs) and organic cation transporters (OCTs).
32
What is active transport, and why is it significant for excretion?
Active transport involves the use of ATP to move xenobiotics against their concentration gradient. It is important for excretion in organs like the brain, liver, and kidneys. Major families include multi-drug resistance proteins (MDRs and MRPs) and breast cancer resistance protein (BCRP).
33
What are the main routes of gastrointestinal tract absorption for xenobiotics?
Gastrointestinal tract absorption involves high levels of capillaries, with most absorption occurring in the small intestine due to its high surface area. It is a crucial route for dietary exposure via food and water.
34
Why is inhalation an important route of absorption for certain xenobiotics?
Inhalation is important for gases, vapors, and particulates because the lung's large surface area and extensive capillary network facilitate rapid absorption.
35
How does dermal (skin) absorption work, and what factors influence it?
Dermal absorption is limited by the skin's barrier properties. Only highly lipophilic chemicals or those applied to damaged skin can readily penetrate.
36
What are some clinical and experimental routes of exposure?
Clinical and experimental routes of exposure include various types of injections, such as intravenous, intramuscular, and subcutaneous injections, used for specific research or therapeutic purposes.
37
What are the different locations in the body where a xenobiotic is distributed referred to as?
They are referred to theoretically as compartments.
38
What follows the initial absorption of a xenobiotic to the "central compartment" (systemic circulation)?
It is followed by distribution to "peripheral compartments" (e.g., liver, brain, other organs, and tissues).
39
Why is there an immediate rapid distribution of lipid-soluble xenobiotics throughout the body after entry into the systemic circulation?
Because lipid-soluble xenobiotics can rapidly distribute, especially into well-perfused tissues.
40
What are the four main factors influencing the distribution of xenobiotics in the body?
Blood flow (perfusion) to a given organ/tissue: The more blood flow to an organ, the more xenobiotic is delivered. Examples of high perfusion tissues are muscles, heart, liver, kidney, and brain, whereas adipose tissue is an example of low perfused tissue.
Physicochemical properties of the xenobiotic: Includes lipid solubility, pKa, and molecular size.
Binding of xenobiotics to plasma proteins and cellular binding proteins.
Barriers to distribution.
41
What is the most abundant plasma protein, and what is its role in xenobiotic binding?
Albumin is the most abundant plasma protein, and xenobiotics have varying affinities for binding to it
42
What is the significance of the free:bound equilibrium in blood plasma?
Only the free xenobiotic can diffuse out of the bloodstream into tissues because plasma proteins are large and cannot cross capillary walls.
43
Explain the dynamic nature of plasma protein binding with xenobiotics.
As free xenobiotics diffuse from the blood to tissues, more is released from plasma proteins until tissue sites are saturated. Additionally, as free xenobiotics are excreted, more is released from plasma proteins to maintain the equilibrium.
44
How does albumin function as a 'bus' for xenobiotics?
Albumin has many binding sites for xenobiotics, with weak chemical bonds and interactions, but it shows a certain affinity depending on the amino acid sequence. It binds both endogenous and exogenous compounds.
45
Which organs have high binding capacity for certain xenobiotics?
The liver and kidney have high binding capacity for certain xenobiotics.
46
Why is adipose tissue significant in xenobiotic storage, and what factors should be considered?
Adipose tissue (fat) is an important storage depot for highly lipophilic xenobiotics (e.g., persistent organic pollutants). Factors to consider include differences between lean and obese individuals, and lactation, as breast milk is high in fat and can accumulate lipophilic drugs, potentially exposing neonates.
47
How does bone interact with certain xenobiotics?
Bone binds certain xenobiotics, such as heavy metals (e.g., lead). Lead mimics calcium, so it is stored in bones, which is considered the ultimate resting place for lead exposure.
48
What is the blood-brain barrier (BBB), and why is it significant for xenobiotic distribution?
The BBB is a major barrier to many xenobiotics due to tightly joined endothelial cells surrounding the CNS and active (ATP-dependent) transporters for removal (e.g., MDR, MRP, BCRP). It is not fully developed in embryos and newborns, which has important toxicological implications.
49
What must be assumed about the placental "barrier" concerning xenobiotics?
It must be assumed that any xenobiotic entering maternal circulation is capable of crossing the placenta unless proven otherwise, especially if it is lipid soluble. Xenobiotics are extensively tested for their ability to cross the placenta and cause teratogenic effects in offspring.
50
What is the definition of volume of distribution (VD)?
VD is the apparent fluid volume in which a xenobiotic appears to be dissolved, indicating how widely a xenobiotic is distributed throughout the body. It is a proportionality constant used to compare the distribution of xenobiotics, especially pharmaceuticals.
51
How is VD calculated?
VD = total xenobiotic dose (mg) /
plasma xenobiotic concentration (mg/L)
52
What does a high VD indicate about a xenobiotic?
A high VD indicates extensive distribution of the xenobiotic and a high affinity for tissues.
53
What does a low VD indicate about a xenobiotic?
A low VD indicates that the xenobiotic is restricted mainly to blood plasma, often due to high plasma protein binding.
54
What is biotransformation?
Biotransformation is the enzyme-catalyzed conversion of one xenobiotic into another.
55
Why is biotransformation important in toxicology?
Biotransformation is the most important determinant of the duration of action of xenobiotics in the body.
56
What is the difference between detoxification and bioactivation?
Detoxification: Biotransformation results in a less toxic metabolite, which is by far the most common outcome.
Bioactivation: Biotransformation results in a more toxic metabolite, a cornerstone of mechanistic toxicology.
57
Why is the lipophilic nature of xenobiotics both an advantage and a hindrance?
While the lipophilic nature allows diffusion across cell membranes and access to their sites of action, it hinders their elimination from the body due to reabsorption from kidney tubules back into systemic circulation.
58
What is the purpose of biotransformation in terms of xenobiotic elimination?
The purpose is to convert lipophilic xenobiotics into highly water-soluble metabolites, which are easily excreted from the body (mainly in urine and to a lesser extent bile/feces).
59
What are the two main types of biotransformation reactions?
Phase 1 Reactions: Involve the modification of the xenobiotic molecule mainly by oxidation (e.g., addition of an -OH group), increasing water solubility.
Phase 2 Reactions: Involve synthetic reactions that conjugate the xenobiotic with a highly polar (very water-soluble) endogenous compound in the cell (e.g., a carbohydrate, sulphate, or acetate).
60
What is the typical sequence of biotransformation for a xenobiotic?
A xenobiotic is often biotransformed sequentially through both Phase I and Phase II reactions.
61
Why is the liver considered the most important site for xenobiotic transformation?
The liver is the primary "detox organ" with high expression of a wide variety of enzymes that are essential for biotransformation.
62
What are some key Phase I and Phase II biotransformation reactions?
Phase I Reaction: Oxidation.
Phase II Reactions: Sulphation, Glucuronidation, Glutathione conjugation, Acetylation
63
What are cytochrome P450-dependent monooxygenases (CYPs), and why are they important in Phase I biotransformation?
CYPs, also known as mixed-function oxidases, are the major Phase I oxidative enzymes. They are crucial because they catalyze the insertion of an oxygen atom into the xenobiotic molecule, often adding or exposing a polar functional group (e.g., -OH, -COOH, -NH2) to increase water solubility.
64
Where are CYP enzymes located within cells?
CYP enzymes that biotransform xenobiotics are located on the smooth endoplasmic reticulum.
65
hat is the significance of the term "monooxygenase" in the context of CYP enzymes?
The term "monooxygenase" indicates that these enzymes catalyze the insertion of one oxygen atom into the xenobiotic molecule.
66
How many different CYP enzymes have been identified, and how are they categorized?
More than 100 different CYP enzymes have been identified. They are categorized into families (e.g., CYP1, CYP2, CYP3), subfamilies (e.g., CYP1A, CYP2E, CYP3A), and specific enzymes (e.g., CYP1A2, CYP2E1, CYP3A4) based on the DNA sequence similarity of the genes coding for these enzymes.
67
Why are CYP enzymes described as "versatile" and "unique"?
CYP enzymes are versatile and unique due to their broad and overlapping substrate specificities. One enzyme can biotransform many xenobiotics (broad specificity), and one xenobiotic can be biotransformed by several enzymes (overlapping specificity).
68
What are some key CYP enzymes important in the human liver and other animals?
CYP2E1 and CYP3A4 are particularly important in the human liver and other animals.
69
What are the two possible outcomes of biotransformation by CYP enzymes?
Detoxification: Inactivation of a xenobiotic, resulting in a less toxic metabolite.
Bioactivation: Conversion of a xenobiotic to a more pharmacologically or toxicologically active metabolite.
70
Provide an example of biotransformation resulting in a metabolite with greater pharmacological or toxicological activity.
An example is the conversion of phenacetin to acetaminophen, where the enzyme cleaves the alkyl group (CH3CH2) to expose the hydroxyl group on the molecule.
71
What is a common reaction in Phase I biotransformation, and what does it involve?
A common reaction is hydroxylation, which involves the addition of a hydroxy group (-OH) to a carbon atom in the xenobiotic molecule.
72
Why did vertebrate animals evolve the GI tract, and what was its significance regarding toxic substances?
The evolution of the GI tract provided a major route of exposure to toxic substances (e.g., plant toxins). To survive, animals had to evolve a strategy to intercept and detoxify these potentially lethal substances.
73
What role does the hepatic portal venous system play in first-pass biotransformation?
The hepatic portal venous system delivers all substances absorbed from the GI tract to the liver before they reach the systemic circulation. The liver has extensive biotransformation capacity to detoxify these substances.
74
What is the "First-Pass Effect"?
The First-Pass Effect refers to the phenomenon where certain drugs (and xenobiotics) are almost completely inactivated (>90%) after oral ingestion due to biotransformation in the liver and intestines before reaching systemic circulation.
75
Why are certain drugs not given orally?
Certain drugs are not given orally because they undergo significant first-pass metabolism, resulting in their inactivation. For example, nitroglycerin is given sublingually to bypass the first-pass effect.
76
What is the equation for oral bioavailability, and what does it represent?
Oral bioavailability is the fraction of an orally administered drug that reaches the systemic circulation in an unchanged form. It is calculated as:
Bioavailability = AUCoral / AUCiv, where AUC stands for the area under the curve, representing the drug's concentration over time.
77
What is the primary purpose of Phase II biotransformation reactions?
The primary purpose of Phase II biotransformation reactions is to significantly increase the water solubility (and thus excretability) of xenobiotics by adding a large water-soluble group to an existing polar functional group on the molecule
78
How do Phase I and Phase II reactions differ in their impact on xenobiotic excretion?
Phase I reactions may increase water solubility, but not enough to make the xenobiotic readily excretable. The major increase in excretion occurs after Phase II reactions, which further enhance water solubility.
79
What is glucuronidation, the enzymes and cofactors involved, and why is it significant in Phase II biotransformation?
Glucuronidation is the major Phase II biotransformation pathway in mammals and most vertebrates. It requires the enzyme UDP-glucuronosyl transferase (UGT) and the cofactor UDP-glucuronic acid. This process adds a glucuronic acid molecule to the xenobiotic, increasing its water solubility.
80
Where are the enzymes for glucuronidation located?
The enzymes for glucuronidation are located on the smooth endoplasmic reticulum (ER) membrane.
81
What enzyme and cofactor are involved in sulfation?
The enzyme sulfotransferase (ST) and the cofactor PAPS are involved in sulfation. This process transfers a sulfate group onto the xenobiotic, increasing its water solubility.
82
What enzyme and cofactor are involved in acetylation?
The enzyme N-acetyltransferase (NAT) and the cofactor acetyl coenzyme A are involved in acetylation. This process transfers an acetyl group to a nitrogen atom on the xenobiotic, producing a very polar and highly soluble metabolite.
83
Why is glutathione conjugation important?
Glutathione conjugation is our most important defense against reactive electrophiles (reactive oxygen species (ROS) and epoxides) and against toxicity. These reactive species are produced continuously in our cells due to the aerobic environment.
84
What enzyme and cofactor are involved in glutathione conjugation?
The enzyme glutathione s-transferase (GST) and the cofactor glutathione (GSH) are involved in glutathione conjugation. GST is very abundant in liver cells, and GSH is present at millimolar concentrations in most cells, indicating its high importance.
85
Describe a glutathione reaction?
Converts an epoxide to an OH and a sugar
86
What are enzyme induction and inhibition, and why are they relevant in toxicology?
Enzyme induction increases the activity of CYP and Phase II enzymes, while inhibition decreases their activity. These processes are relevant because they affect the duration of xenobiotic action and interactions. Depletion of cofactors (e.g., glutathione) can also play an important role.
87
What are intraspecific differences, and how do they influence biotransformation?
Intraspecific differences are genetic variations within a population. These differences can result in subsets of the population being "poor metabolizers" or "rapid metabolizers." A classic example is variations in alcohol dehydrogenase (ADH) in humans.
88
What are interspecific differences, and can you provide examples?
Interspecific differences are variations between species. Examples include:
Cats are poor glucuronidators (UGT).
Dogs are poor acetylators (NAT).
Pigs are poor sulfators (ST).
89
How do sex and age influence enzyme activities related to biotransformation?
Sex-specific differences can occur in certain CYP enzymes. Generally, very young and old individuals have lower enzyme activities, affecting biotransformation.
90
How can diet influence biotransformation?
Certain dietary ingredients can induce or inhibit Phase I or Phase II enzymes. For example, grapefruit juice inhibits CYP3A4 in humans, affecting drug metabolism.
91
What impact does underlying disease have on biotransformation?
Diseases, especially those affecting liver function (e.g., hepatitis or cirrhosis), can impair biotransformation of xenobiotics, leading to altered drug metabolism and potential toxicity.
92
Describe the difference between an AUC of an IV administration vs. an oral adminstration?
IV: high increase and sharp decrease and eventually tapers off (inverse exponential)
Oral: looks more like a hill
93
Why are drug interactions a major cause of adverse responses?
Drug interactions can significantly alter the pharmacokinetics and pharmacodynamics of drugs, leading to unexpected side effects or reduced efficacy.
94
Why is renal excretion the most important xenobiotic elimination pathway in terrestrial vertebrate animals?
Renal excretion is crucial because the kidneys filter and remove waste products and xenobiotics from the bloodstream, maintaining homeostasis.
95
What are the three processes involved in changing the blood level of a xenobiotic in renal excretion?
Glomerular filtration
Tubular reabsorption
Tubular secretion in kidney tubules
96
What is the role of glomerular filtration in renal excretion?
Glomerular filtration involves filtering blood through the glomeruli, where gaps in the filtration membrane allow the passage of small molecules, including xenobiotics.
97
What is tubular reabsorption, and why is it significant?
Tubular reabsorption is the process by which water and solutes are reabsorbed from the kidney tubules back into the bloodstream, reducing the amount of fluid and xenobiotics that are ultimately excreted.
98
What is tubular secretion, and where does it primarily occur?
Tubular secretion involves the active transport of xenobiotics from the blood into the filtrate in the kidney tubules, primarily occurring in the proximal convoluted tubule.
99
What are OATs and CATs, and why should one beware of mimics?
OATs (organic anion transporters) and CATs (cation transporters) are involved in transporting xenobiotics across cell membranes. Mimics can interfere with these transporters, leading to altered xenobiotic concentrations in cells.
100
What happens when the concentration of a xenobiotic in a cell increases due to inhibited excretion?
The xenobiotic concentration in the cell increases because it cannot be pumped out as readily as it can be pumped in, potentially leading to toxicity.
101
How much plasma is filtered daily by the kidneys, and how much water is excreted?
About 180 liters of plasma are filtered daily by the kidneys, with most water being reabsorbed, resulting in approximately 1 liter of water being excreted.
102
Where in the kidney does most water reabsorption occur?
Most water reabsorption occurs in the Loop of Henle.
103
What types of xenobiotics are available for filtration and passive diffusion across cell membranes?
Only the unbound xenobiotics are available for filtration, and only the nonionized forms can passively diffuse across cell membranes.
104
Why is biliary excretion important for certain xenobiotic molecules? .
Biliary excretion is important for larger xenobiotic molecules (molecular weight > 300 g/mol) as it involves facilitated and active transport mechanisms similar to the kidneys
105
What role does the hepatocyte play in biliary excretion?
Hepatocytes, or liver cells, play a crucial role in processing xenobiotics absorbed from the GI tract, delivering them into the bile for excretion.
106
What is enterohepatic cycling, and what impact does it have on xenobiotic half-life and toxicity?
Enterohepatic cycling involves the reabsorption of xenobiotics or their metabolites excreted in bile back into the liver. This can increase the half-life of a xenobiotic and exacerbate liver toxicity if toxic metabolites are continuously cycled.
107
How does biliary excretion affect the elimination and duration of action of drugs with a molecular weight > 300?
Drugs and drug metabolites with a molecular weight > 300 may be excreted via bile, stored in the gallbladder, delivered to the intestines, and then reabsorbed, reducing their elimination and prolonging their half-life and duration of action in the body.
108
What type of xenobiotics are primarily excreted through pulmonary excretion?
Pulmonary excretion is important for volatile and gaseous xenobiotics (e.g., ammonia gas).
109
How is ethanol excreted through the lungs, and what practical application does this have?
Approximately 2% of ethanol is excreted in expired air, which is the basis for breathalyzer tests used to measure blood alcohol levels.
110
How does lactation serve as a route of xenobiotic excretion, and why is this significant?
Lactation can significantly eliminate lipophilic xenobiotics, ranging from 0.1 to 2% of the maternal dose, which is important for neonatal exposure and food product safety (e.g., milk, cheese).
111
What are some minor routes of xenobiotic excretion?
Saliva
Sweat
Hair, nails, and other keratinous body parts in animals
112
What marks the initiation of chemically induced cancer?
The altered DNA in the first two cells marks the initiation of chemically induced cancer.
113
Why is the liver capable of regenerating itself?
The liver can regenerate itself because it can repair pathological effects.
114
What often happens when two or more xenobiotics are coadministered?
The coadministration of two or more xenobiotics is often associated with altered excretion of one or more of the xenobiotics.
115
Define summation (additivity) in the context of xenobiotic interactions.
Summation (additivity) occurs when the combined effect of two xenobiotics is equal to the sum of their individual effects (e.g., 2 + 2 = 4).
116
What is synergism in xenobiotic interactions?
Synergism occurs when the combined effect of two xenobiotics exceeds the sum of their individual effects (e.g., 2 + 2 = 10).
117
Explain potentiation in the context of xenobiotic interactions.
Potentiation occurs when a xenobiotic with no effect intensifies the effect of a second xenobiotic (e.g., 2 + 0 = 10).
118
What does antagonism mean in xenobiotic interactions?
Antagonism occurs when the combined effect of two xenobiotics is less than additive (e.g., 2 + 2 = 1), often due to receptor binding competition.
119
How can interactions during biotransformation affect xenobiotic interactions?
Interactions during biotransformation can involve the induction or inhibition of Phase I and Phase II enzymes, affecting the metabolism of xenobiotics.
120
Describe how interactions during distribution can influence xenobiotic interactions.
Interactions during distribution can involve competition for plasma and cellular binding proteins, leading to the displacement of xenobiotics and an increased free (unbound) fraction, resulting in a greater response.
121
What is the impact of interactions during excretion on xenobiotic interactions?
Decreased clearance due to inhibition of renal excretion often involves competition for renal facilitated transport proteins, affecting the elimination of xenobiotics.
122
How can interactions during absorption affect xenobiotic interactions?
Substances affecting the pH of the GI tract can alter the absorption of xenobiotics, impacting their bioavailability.
123
Why are doses always given in a body weight ratio?
Doses are always given in a body weight ratio to account for individual differences in metabolism and response, ensuring appropriate and effective dosing.
124
Describe the visual of a one compartment model?
One Ka directly into one compartment, and then one Kel exiting the compartment
125
Describe the visual mathematical model of a one compartment model?
Log Cp against Time, a direct negative linear line
126
Describe the visual of a two compartment model?
One Ka directly into one central compartment, and then one K entering the peripheral compartment, one exiting the peripheral compartment into the central compartment, and one final K leaving the central compartment
127
Describe the visual mathematical model of a one compartment model?
Log Cp against Time, a direct negative linear line with a kink
128
What is toxicokinetic modelling?
Toxicokinetic modelling is the mathematical description of the time course of disposition (ADME) of xenobiotics in the body. It hypothesizes that a relationship exists between the toxicological effect of a xenobiotic and its concentration in the systemic circulation.
129
What are the three key concepts in toxicokinetic modelling?
Bioavailability (F)
Volume of Distribution (VD)
Clearance (CL)
130
__________: The fraction of an administered dose of xenobiotic that reaches the systemic circulation in an unchanged form.
Bioavailability
131
___________: The apparent fluid volume in which a xenobiotic appears to be distributed. A low VD indicates the xenobiotic is kept in the systemic circulation, often due to plasma protein binding.
Volume of Distribution
132
________: The overall efficiency of xenobiotic removal from the body, measured in volume of blood cleared per unit time (e.g., CL = 100 mL/min means 100 mL of blood is cleared of the xenobiotic every minute).
Clearance
133
Which types of xenobiotics typically follow a one-compartment model?
Very lipophilic xenobiotics often follow a simple one-compartment model, where the rate of absorption (ka) and the rate of elimination (kel) are considered.
134
What is the equation used in the one-compartment model to describe blood plasma concentration (Cp)?
The equation is: 𝐶𝑝 = 𝐶0 ⋅ 𝑒 ^(−𝑘𝑒𝑙 ⋅ 𝑡)
where Cp is the blood plasma concentration, C0 is the initial concentration at time zero, and kel is the elimination rate constant.
135
How is the elimination rate constant (kel) determined in a one-compartment model?
Kel is determined from the slope of a log blood plasma concentration (Log Cp) vs. time graph.
136
What is the formula for calculating xenobiotic half-life (T1/2)?
The formula for calculating half-life is:
𝑇1/2 = 0.693 / 𝑘𝑒𝑙
137
How is clearance (CL) calculated in a one-compartment model?
Clearance (CL) is calculated as:
𝐶𝐿 = 𝑉𝐷 ⋅ 𝑘𝑒𝑙
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What is the general rule for xenobiotic elimination based on half-lives?
The general rule is that after 7 half-lives, approximately 99% of the xenobiotic is eliminated from the body
139
What defines the two-compartment model for xenobiotics?
The two-compartment model defines the systemic circulation as one compartment and everything outside the systemic circulation (peripheral) as another compartment.
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Why is the two-compartment model considered a simplification?
It is considered a simplification because it assumes everything outside the bloodstream is a single compartment, which is not technically true. In reality, there are multiple tissues and compartments involved.
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How does the two-compartment model handle the movement of xenobiotics?
The two-compartment model includes individual rate constants for the movement of xenobiotics into and out of the peripheral compartment.
142
Describe visually a first order kinetics graph?
Plasma drug concentration vs. time. Inverse exponential shape
143
Describe visually a zero order kinetics graph?
Plasma drug concentration vs. time. Negatively linear graph
144
What is the equation used in the two-compartment model to describe blood plasma concentration (Cp)?
𝐶𝑝 = 𝐴𝑒^(−𝛼𝑡) + 𝐵𝑒^(−𝛽𝑡)
where A and B are the y-intercepts, α is the slope of the distribution phase, and β is the slope of the elimination phase.
145
What does α represent in the two-compartment model?
α represents the slope of the distribution phase, detailing absorption and distribution.
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What does β represent in the two-compartment model?
β represents the slope of the elimination phase and is also known as the elimination rate constant (Kel) in the one-compartment model.
147
How is xenobiotic half-life (T1/2) calculated in the two-compartment model?
𝑇1/2 = 0.693 / 𝛽
148
How is clearance (CL) calculated in the two-compartment model?
𝐶𝐿 = 𝑉𝐷 × 𝛽
149
What is the general rule for xenobiotic elimination based on half-lives in the two-compartment model?
The general rule is that after 7 half-lives, approximately 99% of the xenobiotic is eliminated from the body.
150
What do PBPK models show us about the complexity of xenobiotic pharmacokinetics?
PBPK models show that the pharmacokinetics of xenobiotics can become very complicated and are often used to understand the kinetics of problem xenobiotics.
151
What is the main characteristic of first-order kinetics?
In first-order kinetics, elimination is proportional to the plasma concentration (Cp), resulting in a characteristic curved response and a sharp decrease/elimination.
152
What is the main characteristic of zero-order kinetics?
In zero-order kinetics, elimination is independent of the plasma concentration (Cp), resulting in a constant elimination rate and a characteristic straight response. This can be dangerous at high exposure levels since elimination can only occur at a constant rate.
153
Provide an example of a substance that follows zero-order kinetics.
Ethanol follows zero-order kinetics.
154
What important distinction should be remembered about log scales in order kinetics vs. compartment models?
There is no logarithm in order kinetics. If there is a log scale, it indicates a compartment model, which is unrelated to order kinetics.
155
When is steady state reached in repeated dosing?
Steady state is typically reached after 4 half-lives of repeated dosing.
156
Is the time to reach steady state dependent on dosage?
No, the time to reach steady state is independent of dosage
157
What factors are proportional to the actual steady-state concentrations?
Actual steady-state concentrations are proportional to dose, dose interval, bioavailability, and clearance.
158
How do fluctuations in steady state relate to the xenobiotic interval?
Fluctuations are proportional to the interval of the xenobiotic. Reduced absorption results in smaller rises in concentration.
159
What model and kinetics do most xenobiotics follow in toxicokinetics?
Most xenobiotics follow a two-compartment model and first-order toxicokinetics.
160
When are physiologically-based pharmacokinetic (PBPK) models used?
PBPK models are used for drugs and toxicants that exhibit "unusual" toxicokinetics and/or are dangerous drugs with a narrow therapeutic window.
161
Why are xenobiotics exhibiting zero-order toxicokinetics considered dangerous?
Xenobiotics exhibiting zero-order toxicokinetics are dangerous because their elimination is constant, which means that at higher doses, the risk of toxicity is significant.
162
What happens when a xenobiotic exhibits first-order kinetics at lower doses and switches to zero-order kinetics at higher doses?
This switch occurs mainly due to the saturation of biotransformation enzymes, leading to constant elimination at higher doses and increased risk of toxicity.
163
What is bioaccumulation?
Bioaccumulation is the net accumulation of a xenobiotic in an organism from all exposure routes (e.g., food, water, air, soil).
164
In which organisms does bioconcentration commonly occur?
Bioconcentration commonly occurs in aquatic organisms such as fishes, crustaceans, and molluscs, where the xenobiotic is accumulated from water only through respiratory surfaces or skin.
165
What is the Bioconcentration Factor (BCF)?
BCF is the ratio of the concentration of a xenobiotic in an organism to the concentration in water:
BCF = [xenobiotic in organism] / [xenobiotic in water]
A greater concentration in the organism indicates bioconcentration
166
When do bioaccumulation and bioconcentration occur?
Bioaccumulation and bioconcentration occur when the rate of xenobiotic absorption exceeds the rate of xenobiotic excretion.
167
What is biomagnification?
Biomagnification occurs when xenobiotic concentrations increase through at least three trophic levels in a food chain.
168
What is the general definition of biomagnification in terms of concentration increase?
Generally, biomagnification involves at least a 10-fold increase in xenobiotic concentration at each step in the food chain.
169
Which xenobiotics are most likely to undergo biomagnification?
Xenobiotics with very high lipophilicity (log Kow > 5) are most likely to undergo biomagnification
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What are "Persistent Organic Pollutants" (POPs) or "legacy contaminants"?
POPs or legacy contaminants are xenobiotics that can have concentrations in top predators greater than 1,000,000 times the concentration in the environment.
