Absorption

What is Toxicokinetics

the determination of the time course of ADME (absorption, distribution, metabolism, excretion) of xenobiotics

Toxicokinetics is essentially “what ___ does to the xenobiotic”

the body

what does the toxicokinetics determine

the concentration of a xenobiotic at its site(s) of action, which is linked to the intensity of its biological effect

what is the most important factor allowing a xenobiotic to diffuse across a cell membrane

Lipophilicity

what other factor’s besides lipophilicity affects a xenobiotic’s ability to cross a membrane

Molecular Size

what are the four ways xenobiotics cross cell membranes

1. Passive Transport

2. Filtration

3. Facilitated Diffusion

4. Active Transport

Which membrane transport mechanism is the most common absorption pathway for xenobiotics

Passive Transport

What is passive diffusion

movement of a xenobiotic across a membrane down its concentration gradient

Does passive diffusion require ATP

No

What is another name for passive diffusion across a cell

Transcellular diffusion

What type of chemicals can readily diffuse through the lipid membrane

Organic lipophilic chemicals (Steroid hormones)

What does Kow measure

The octanol:water partition coefficient, used to measure lipophilicity

What does a high log Kow indicate

Means high lipophilicity and significant potential for accumulation and toxicity → value of >4

What is an example of a xenobiotic with a high log Kow

DDT

What does POP stand for

Persistent organic pollutant

What determines the relatives proportion of ionized vs nonionized forms of a weak acid/base

the pKa of the xenobiotic and the pH of the solution

Which form can passively diffuse across cell membranes

Nonionized form

Which form crosses lipid membranes poorly

Ionized form

For a weak acid, what is the protonated form

HA

Is the protonated form of a weak acid ionized or nonionized

Nonionized

For a weak base, what is the protonated form

BH⁺

is the protonated form of a weak base ionized or nonionized

Ionized

If pka -pH = 1, what is the ratio?

10:1

If pKa - pH = 2, what is the ratio

100:1

If the pKa - pH = 3, what is the ratio

1000:1

What is ion trapping

When a nonionized xenobiotic crosses into an environment where it becomes ionized and is therefore unable to easily cross back

What happens to a weak base when it enters a more acidic environment

it becomes more protonated/ ionized

Why does ionized drug become “trapped”

Because the ionized form cannot easily diffuse back across the lipid membrane

what is an example of ion trapping

A weak-base antibiotic moving from plasma into breast milk, where lower pH causes more of the drug to become ionized

what is filtration (bulk flow)

Movement of a xenobiotic with water through gaps between cells due to a pressure gradient

What is the most important factor for filtration

size

what is filtration also called

Paracellular transport

Does facilitated diffusion require ATP

No

Does facilitated diffusion move down or against the concentration gradient

Down the concentration gradient

What makes facilitated diffusion different from simple diffusion

It requires a transporter

Does active transport require ATP

yes ATP

Does active transport move with or against the concentration gradient

Against

What major protein family is involved in active transport

ATP-binding cassette (ABC) proteins

What are the major routes of xenobiotic exposure discussed

• GI tract/ ingestion

• Inhalation

• Dermal

• Injection

Where does most GI absorption occur

Small intestine because of its high surface area