1
Q
Toxicology
A
multidisciplinary science that “borrows” approaches and techniques from other sciences
2
Q
Paracelsus
A
- Phillipus Aureolus Theophrastus Bombastus von Hohenheim (1493-1541)
- identified central concept of toxicology: the dose-response relationship (the dose defines the poison)
3
Q
ADME
A
Absorption,
Distribution,
Metabolism,
Excretion
4
Q
Toxicokinetics
A
determination of the time course of disposition (ADME) of xenobiotics in the body
“what the body does to the drug”
5
Q
Absorption
A
a) very small hydrophilic chemicals ie. EtOH
b) lipophilic, organic chemicals ie. DDT, PCBs
c) weak, organic acids and bases ie. PPCPs
6
Q
Types of Absorption
A
1) passive diffusion
2) filtration (bulk flow)
3) active transport
4) facilitated diffusion
5) phagocytosis and pinocytosis
7
Q
Passive Diffusion
A
- small hydrophillic particles (water-soluble)
- lipophillic particles(lipid-soluble)
- weak acids and bases
- a chemical follows its C gradient and diffuses across lipid domain
8
Q
Filtration
A
- xenobiotic passes with H2O between cells (pressure gradient)
- cellular gap junctions - nm usually but glomurulus = 70nm for large molecules (kidney - blood filtration ~200L/day)
- BBB has no gap junctions; protects brain from toxicant exposure; recognizes xeno as substrate and sends it back out into blood
9
Q
Active Transport
A
- requires ATP
- pumps xenobiotic against C gradient
- excretion of xenobiotics (liver and kidney)
- ex. P-glycoprotein (multi-drug resistant family; “mdr”) - high quantities in cancer cells
10
Q
Facilitated Diffusion
A
- moves with C gradient
- no energy required
- important for endogenous compounds (nutrients, electrolytes, essential elements) - xenos can mimic these
ex. PB2+ mimics muscle contraction regulated by Ca2+
11
Q
Phagocytosis and Pinocytosis
A
- membrane engulfs substrate on inside and removes it
- good for fine particles in the lungs
12
Q
Routes of Absorption
A
1) GI Tract - ingestion
2) Lungs - inhalation
3) Skin - dermal
4) Other - intravenous (veins)
subcutaneous (under skin - many capillaries)
intramuscular (muscle)
intraperitoreal (body cavity)
13
Q
Ingestion
A
- through GI tract by something we are or drank
- most important/common
- lipophillic toxicants
- can occur anywhere in GI tract but most commonly in small intestine due to fine capillaries
- oral administration easy, economic, safe but variable absorption, and relies on patient complience
14
Q
Inhalation
A
-through lungs in the form of gas or vapour
alveoli (sacs at bottom of lungs) - blood - tissues
- rapid absorption, avoidance of systemic side effects of some drugs
- patient compliance, regulation of dose administration
15
Q
Dermal
A
-absorbed through the skin, which provides a thick layer of protection against xenos
16
Q
Intravenous
A
- injected into veins
- complete absorption, accurate titration dose, can give large volumes, can give tissue irritants
- increased risk of adverse reaction, requires sterile technique, requires vascular access
- completely absorbed
17
Q
Subcutaneous
A
- injected under the skin where there are lots of capillaries
- almost complete absorption, repository formulations for slow release and prolonged action
- not large volumes, may cause tissue irritation or pain
18
Q
Intramuscular
A
- injected into the muscle
- almost complete absorption, repository formulations for slow release and prolonged action
- no large volumes, may cause tissue irritation or pain
19
Q
Intraperitoneal
A
-injected into the body cavity
20
Q
Distribution - 4 Main Factors
A
1) lipophlicity
2) tissue perfusion (blood flow) - not as much blood flows to adipose
3) plasma and cellular protein binding
4) barriers - BBB
21
Q
Endocrine Disrupting Chemicals
A
- “hormone mimics”
- compete with natural hormones for binding sites - can displace and alter natural hormones
- hormones bind tightly
22
Q
Distribution - Storage Sites
A
1) plasma proteins - free and bound forms
2) liver and kidney
3) fat (adipose tissue)
4) bone
23
Q
Plasma Proteins - Storage Site
A
- a fraction of xenos bound can be excreted . Only free form can diffuse out of blood stream
- as free moves away, bound will release to balance equilibrium
24
Q
Liver and Kidney - Storage Site
A
- cellular proteins that bind xenos
ex. metallothianine - cd - major target organ of cadmium is kidney (get cd buildup within cell)
25
Fat- Storage Site
- high logKow (>5) - "Persistent Organic Pollutants" (POPs)
- increase body fat will have increase on exposure to POPs
- Lactation - xenobiotics accumulate in breast milk and are eliminated through breast feeding (exposure route for baby)
26
Bone - Storage Site
-lead mimics Ca
27
Barriers to Distribution
1) BBB - not fully developed at birth; MeHg can penetrate
| 2) placental barrier during gestation
28
Volume of Distribution
- the apparent fluid volume in which the xeno appears to be dissolved (how widely the xeno is distributed throughout the body)
- a "proportionality constant" used to compare xeno distribution
Vd = total drug dose (mg)/plasma drug C (mg/L)
29
Biotransformation
- enzyme-catalyzed conversion of 1 xeno into another
- most important determinant of the duration of action of xenos in the body
- liver is most important site
30
Detoxification
when biotransformation results in a LESS toxic metabolite
31
Bioactivation
when biotransformation results in a MORE toxic metabolite
32
Redundant Pathway
-if one pathway does not work, another one will take over to do its job
33
Induction
increased bioactivation of toxic metabolites
34
Inhibition
decrease in detoxification of xenos
| ex. grapefruit juice is effective inhibitor of CYP
35
Oral Bioavailability
fraction of an orally administered drug that reaches the systemic circulation in an unchanged form (100% bioavailable)
36
Glucuronidation
Enzyme: UDP-glucuronosyl transferase (a sugar)
Cofactor: UDP-glucuronic acid
37
Sulfation
Enzyme: sulfotransferase
Cofactor: 3'phosphoadenasine - 5' phosphosulfate (PAPS)
38
Acetylation
Enzyme: acetyltransferase (N-acetyltransferase)
Cofactor: acetyl-coenzyme A
39
Glutathione S-Transferase (GST)
Enzyme: glutathione s-transferase
Cofactor: glutathione (GSH)
- one of our most important defenses against reactive electrophiles
- conjugates rearranged to mercapturic acid and commonly extcreted in bile
40
Genetic and Environmental Factors Influencing Biotransformation
1) enzyme induction and inhibition, also cofactor depletion (GSH)
2) intraspecific differences
- enzyme polymorphism (mutation)
3) interspecific differences
- mammals/birds >reptiles/amphibians/fish>invertebrates
4) gender, age, diet
- CNS not fully developed when young
- testosterone main hormone in men; estrogen in women
- grapefruit juice inhibits CYP 3A4
5) disease
- underlying pathology/reduced ability to excrete xenos
41
Extcretion
- renal is the most important
- biliary: important for xenos with MW>350 (large molecules, smaller ones go through kidney)
- pulnomary: gases and volatile chemicals ex. EtOH
- lactation: xenos in breast milk; exposure to offspring
- sweat, saliva,hair, nails
42
All the rats died and all the mice lived. Give 5 reasons why.
1) increase absorption in mice due to intestine or transporters
2) mice bind xeno to plasma proteins better
3) different expressions of biotransformation
4) increased body fat
5) rapid excretion
6) mice are more alkaline than the rats
7) different metabolic pathways
43
Renal Excretion
3 processes involved:
1) glomerular filtration (only free form excreted)
2) tubular filtration (lipid soluble with passive diffusion back into blood stream)
3) tubular secretion
44
Metabolic Plasmadosis
CO2 buildup in blood, lowering blood pH
45
Xenobiotic Interactions
the coadministration of 2 or more xenobiotics is often associated with altered clearance of 1 (or more) of the xenobiotics; summation (additivity), synergism, potentiation, antagonism
46
Summation (Additivity)
no interaction; most common; sum of their effects
2+2 = 4
47
Synergism
two chemicals work together to synergise and create a greater than additive effect
2+2 = 10
ex. alcohol+barbituates
ex. taking 2 different painkillers - morphine and advil: they target different aspects of pain so you get a greater than additive effect
48
Potentiation
2+0 = 10
ex.drinking grapefruit juice inhibits biotransformation of some drugs so you get a greater effect for that drug
49
Antagonism
ess than additive effect; reduced effect; one drug blocks the ability of the other to bind to its receptor
2+2 = 1
50
Xenobiotic Interaction during Absorption
-changing pH of the GI tract
51
Xenobiotic Interaction during Distribution
- plasma protein binding is major
- competition for plasma proteins
- competition for tissue-binding
52
Xenobiotic Interaction during Biotransformation
- induction and inhibition of an enzyme
| - inhibition of an enzyme = decreased metabolism = increased toxic effect
53
Xenobiotic Interaction during Excretion
-OAT, mdr
54
3 Concepts of Toxicokinetics
1) bioavailability - fraction of a drug that reaches the systemic circulation unchanged
2) volume of distribution - how widely the xeno is distributed throughout the body
3) clearance - efficiency of elimination
55
One-Compartment Model
- animal body has single homogeneous compartment
- ka = absorption rate -kel = elimination rate
- a straight line on the graph means the drug follows a 1C model
- 1st order kinetics = elimination is proportional to Cp
- Cp = plasma concentration -kel of log graph = 2.303 x slope
- overall equation: Cp = Co x e^(-kel x t)
- half life = 0.693/kel(min-1): after 7 half lives, 99% is eliminated
56
Two-Compartment Model
- ka = absorption rate - k12 = distribution rate
- k21 = returning to blood stream - k10 = elimination rate
- Cp = Ae^(-alpha x t) + Be^(-beta x t)
- slope above kink in graph = alpha (A, D)
- slope below kink in graph = beta (M, E) = kel
57
Steady State
- attained after approximately four half-times
- time to SS independent of dosage
- concentrations proportional to dose/dosage interval/ proportional to F/CL
- fluctuations proportional to dosage interval/ 1/2 time (blunted by slow absorption)
58
First order kinetics:
Elimination is proportional to Cp
59
Zero order kinetics:
Elimination is independent of Cp (constant elimination)
Tox 300
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