Toxicology - Absorption, Distribution and Excretion

What impacts the passability of a cell membrane (absorption)?

• the fatty environment

  • Water-soluble compounds would not like this

• the lipid bilayer

  • polar heads on the outside

• the outer charge of the membrane

How do chemicals/xenobiotics pass through the cell membrane?

• passive diffusion through membrane phospholipids

• passive diffusion through aqueous pores

• active transport

• facilitated diffusion

• phagocytosis and pinocytosis

What is passive diffusion and filtration?

When small molecules up to 100-200 MW (ethanol, ureum) follow the concentration gradient through the membrane (high to low conc.). It is influenced by lipophilicity, ionisation, and blood flow.

What is the role of ionisation during passive diffusion and filtration?

Weak organic acids or bases are ionized because a chemical with a charge cannot pass the membrane.

Is a chemical more abundant in an ionized or non-ionized state?

Ionized because there is less charge, so it can pass through membranes.

Benzoic acid —> more likely absorbed in stomach

Aniline —> more likely absorbed in intestine

What is the role of blood flow in passive diffusion and filtration?

The blood flow creates a gradient across the membrane and flushes away the chemicals.

What happens during active transport?

Chemicals are moved up a concentration gradient (ATP needed), making it sensitive to metabolic inhibitors. The transport system is selective and has a potential for competitive inhibition.

What is facilitated diffusion?

It does not require energy input and transports molecules down the concentration gradient. But there are two groups of integral membrane proteins involved. Being the carrier proteins (hexose/glucose transporters) and ion channels.

Can a chemical that is not glucose pass through a facilitated glucose transporters?

Yes, if it is bonded to a glucose.

what does phagocytosis and pinocytosis mean and is it energy consuming?

It is cell eating and drinking and requires energy.

What is cell eating and cell drinking?

Cell eating is the ingestion of particles by specialized cells (neutrophils, macrophages).

Cell drinking is the ingestion of drops or small particles (<1 micro. m) by all cells.

What are exposure routes through which chemicals can enter the human body?

• skin

• vein (drug injections)

• gut (eat &drink)

• lungs (inhale)

What is unique about the gut exposure route?

Everything that goes through the gut also goes through the liver.

What is unique about the skin exposure route?

It takes the longest because the skin is a thick barrier.

What body parts are in the gastrointestinal tract when something is consumed through oral exposure?

• mouth

• stomach (acidic)

• duodenum

• ileum

• colon

• rectum

What is oral exposure route dependent on?

• concentration

• duration + level exposure

• area of exposure (villi)

• epithelial layer

• sub epidermal blood flow

• physico-chemical properties

Are the chemicals that end up in our body the same as what we are initially exposed to?

No, they are usually different.

What part are all chemicals taken up oraly first absorbed by?

they are first absorbed by the portal vein and then go to the liver.

Which organ changes chemicals taken up?

The liver.

what is the entrohipatic cylce (first pass effect)?

The liver excretes chemicals (that were initially taken up from the intestine) via the bowel, going back to the intestine.

Does the route of exposure impact the effect of the chemical?

Yes.

What does ADME stand for?

absorption

distribution

metabolism

excretion