3. Absorption, distribution and excretion

What are the five ways Xenobiotics pass through cell membranes?

1. Passive diffusion through the membrane phospholipids

2. Passive filtration through aqueous pores

3. Active transport

4. Facilitated diffusion

5. Endocytosis: phagocytosis and pinocytosis

What are xenobiotics?

Xenobiotics are chemical substances foreign to a biological system, meaning they do not naturally occur or are not produced within an organism

Effect of pH on ionization

• At a low pH, the non ionized version of benzoic acid is more present and therefore passes the membrane better as it doesn’t have a charge'

• For example in the stomach the pH is very low, weak acids like aspirin remain non-ionized and are absorbed easily here. Whereas in the small intestine where the pH is higher they are absorbed much less efficiently.

Passive diffusion and filtration

• Small molecules up to MW 100-200 (ethanol, ureum)

• Down a conc. gradient

• Influenced by:

  • Lipophilicity

  • Ionization (different pH’s cause different charges)

  • Blood flow

Role of blood flow in passive diffusion and filtration

• The blood flow creates a gradient across the membrane

Absorption: active transport

• Chemicals are moved UP a concentration gradient

• The transport system is selective and has the potential for competitive inhibition

• Requires energy (ATP): sensitive to inhibition by metabolic inhibitors

• The transport system is saturated at high substrate concentrations (Tmax)

Facilitated diffusion

• Similar to simple diffusion in the sense that;

  • It does not require energy and

  • transport down a concentration gradient

• Two groups integral membrane proteins involved:

  • carrier proteins (hexose/glucose transporters)

  • Ion channels (Cl^-, Na⁺)

• e.g. flavonoid-glycosides can be absorbed via the glucose transporters in the small intestine

Absorption: phagocytosis and pinocytosis

• Mainly used by the immune system

• Phagocytosis: Cell eating

  • ingestion particles

  • Specialized cells (neutrophils, macrophages)

• Pinocytosis: Cell drinking

  • ingestion of drops or small particles (<1 micrometer)

  • Almost all cells

Uptake kinetics

• Red = passive

  • High concentration difference = high rate of transport

• blue = active

  • Is not dependent on the concentration difference as it is driven by pumps

facilitated diffusion vs active transport graph

• To find the differences in these graphs you need to know the concentration gradient

• Bottom graph = active because it exceeds concentration gradient

Distribution: oral exposure

Gastrointestinal tract: mouth, stomach (acidic), duodenum, ileum, colon, rectum

Dependent on:

• Concentration

• Duration + level exposure

• Area of exposure (vili)

• epithelial layer

• Sub epidermal blood flow

• Physico-chemical properties

First pass effect

• Everything entering our body will end up in the portal vein and into the liver.

• Therefore everything we are exposed to does not enter in the rest of our body

• Therefore not all medicines can be swallowed because the liver will break it down.

ADME

• Absorption

• Distribution

• Metabolization

• Excretion

distribution in the body

• Blood flow

• diffusion out of capillary bed into the cells

• Active transport into cells

• Volume of distribution

• Binding to plasma and tissue proteins

• Storage in tissue (fat, liver, bone)

• Specific barriers (Blood-brain barrier)

Distribution can be uneven, this can contribute to toxicity in specific tissue

Examples of toxins being stored in the body

• Toxicants and fatty acids reversibly bind to albumin which prevents them from being filtered by the kidney

• Fluorine being stored in bones

• Dioxins being stored in fat

Blood brain barrier

• No fenestrae

  • While standard capillaries throughout the body contain small openings called fenestrae to allow for easy exchange of substances, BBB-forming endothelial cells are tightly sealed to restrict passive diffusion

• Less permeable due to tighter junctions

• Low protein content of interstitial fluid

• Mainly active transport

• Not fully developed at birth: toxicity for newborn

Placenta

• Thought of as a barrier but is not

• An organ separating the mother from the infant

• Toxic agents: pass by passive diffusion

• e.g. alcohol easily crosses the placental barrier

Excretion

• Kidney: urinary excretion

• Liver: via bile, fecal excretion

• lung: exhalation

• Other routes:

  • Mother’s milk

  • Sweat and saliva

Definition toxicokinetics

The study of how a substance gets into the body and what happens to it while it is there.

Focus is on what the body does to the chemical

Toxicodynamics definition

Refers to the dynamic phase of a toxicological interaction. It is defined as the phase in which the toxic substance interacts with its corresponding primary receptors or target molecules.

Focus is on what the chemical does to the body

Role of ionization in absorption

• Weak acids and bases are generally lipophilic enough to pass through lipid membranes only when they are in their non-ionized (undissociated) form. Highly dissociated or ionized compounds are typically hydrophilic and are absorbed poorly, if at all, unless the epithelial barrier is damaged