Disposition of xenobiotics

composite of absorption, distribution, biotransformation, & elimination

.Skin 2.Lungs 3.Alimentary canal

To become toxic, must cross biological membranes

.Passive transport 2.Specialized transport

passive movement from high to low concentration 1.Paracellular diffusion 2.Transcellular diffusion 3.Filtration

Transport rate depends on

partition coefficient, P - determined by [X] in octanol/ [X] in water (describes degree of lipid solubility) water = 1 solvent, 1-octanol = 2nd solvent

many weak organic acids or bases ionize in solution •pH at which acid or base is 50% ionized = its pKa or pKb

Brönsted-Lowry acid-base theory

acid = proton (H+) donor, base = proton acceptor •Ionized & nonionized forms of an organic acid represent acid-base pair

CELL MEMBRANES: SPECIAL TRANSPORT

Large or lipid-insoluble compounds, including xenobiotics, require special transporters

Xenobiotics transporter classes 1.ATP-binding cassette

(ABC) transporters •Active transport •7 subfamilies (A - G) •MDR1 (B subfamily), C subfamily

•Facilitated diffusion •43 families •Organic-anion transporting peptides (OATPs), Peptide transporters (PEPTs), Multidrug and toxin extrusion (MATE) transporters

Process by which toxicants/xenobiotics cross body membranes to enter bloodstream is same as other substances

ABSORPTION Primary sites

.Gastrointestinal tract 2.Lungs 3.Skin

Administration routes

1.Enteral (sublingual, oral, & rectal) 2.Parenteral (intravenous, intraperitoneal, intramuscular, subcutaneous

most common route of unintentional toxicant exposure (especially children) & intentional overdoses

Organic acids & bases

tend to be absorbed by simple diffusion

Amount of chemical entering systemic circulation depends on

1.Amount absorbed into GI cells 2.Biotransformation by GI cells 3.Extraction by liver into bile (w/ or w/o biotransformation)

Presystemic elimination (first-pass effect)

4.Chelation alters lipid solubility, thus absorption 5.Inhibition of transporters

Nose acts as “scrubber” Mucosa covered by film of fluid; hydrophilic gas molecules may dissolve in fluid & be retained in the nose = ¯ systemic exposure, risk to nasal tissues

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toxicology ch 5

Question	Answer
Disposition of xenobiotics	composite of absorption, distribution, biotransformation, & elimination
Primary barriers	.Skin 2.Lungs 3.Alimentary canal
To become toxic, must cross biological membranes	.Passive transport 2.Specialized transport
Fick’s law	passive movement from high to low concentration 1.Paracellular diffusion 2.Transcellular diffusion 3.Filtration
Transport rate depends on	partition coefficient, P - determined by [X] in octanol/ [X] in water (describes degree of lipid solubility) water = 1 solvent, 1-octanol = 2nd solvent
Arrhenius’ theory	many weak organic acids or bases ionize in solution •pH at which acid or base is 50% ionized = its pKa or pKb
Brönsted-Lowry acid-base theory	acid = proton (H+) donor, base = proton acceptor •Ionized & nonionized forms of an organic acid represent acid-base pair
CELL MEMBRANES: SPECIAL TRANSPORT	Large or lipid-insoluble compounds, including xenobiotics, require special transporters
Xenobiotics transporter classes 1.ATP-binding cassette	(ABC) transporters •Active transport •7 subfamilies (A - G) •MDR1 (B subfamily), C subfamily
.Solute carriers	•Facilitated diffusion •43 families •Organic-anion transporting peptides (OATPs), Peptide transporters (PEPTs), Multidrug and toxin extrusion (MATE) transporters
ABSORPTION	Process by which toxicants/xenobiotics cross body membranes to enter bloodstream is same as other substances
ABSORPTION Primary sites	.Gastrointestinal tract 2.Lungs 3.Skin
Administration routes	1.Enteral (sublingual, oral, & rectal) 2.Parenteral (intravenous, intraperitoneal, intramuscular, subcutaneous
Oral ingestion	most common route of unintentional toxicant exposure (especially children) & intentional overdoses
Organic acids & bases	tend to be absorbed by simple diffusion
Amount of chemical entering systemic circulation depends on	1.Amount absorbed into GI cells 2.Biotransformation by GI cells 3.Extraction by liver into bile (w/ or w/o biotransformation)
Presystemic elimination (first-pass effect)	4.Chelation alters lipid solubility, thus absorption 5.Inhibition of transporters
Gases & Vapors	Nose acts as “scrubber” Mucosa covered by film of fluid; hydrophilic gas molecules may dissolve in fluid & be retained in the nose = ¯ systemic exposure, risk to nasal tissues

Created by: aceofspades08

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