lec 3- absorption, distribution and excretion

what does the degree of interaction between toxic substance and receptors depend on

1. exposure phase: how much of the substance is around you and how much you take in.

2. kinetic phase/ toxikinetics (ADME): what happens inside the body

3. dynamic phase: toxicodynamics: actual damage

EKG

whats external exposure vs external load/dose

The exposure phase. With regard to this phase, a distinction is made between external exposure,
which is defined as the amount or concentration of a substance present in the organism's
environment, and external load (dose), which corresponds to the amount of substance available for uptake by the organism.

How is the membrane described as

fluid mosaic model

what is fluid character of membrane determined by

The fluid character of the membranes is determined largely by the structure and relative abundance of unsaturated fatty acids.

more saturated fatty acids what does it mean

The more unsaturated fatty acids membranes contain, the more fluid-like they
are, facilitating more rapid active or passive transport

what are the ways toxicants/ xenobiotics can pass cell membrane

1. passive diffusion through the membrane phospholipids 
2. passive filtration trough aqueous pores 
3. active transport 
4. facilitated diffusion 
5. Endocytosis: phagocytosis and pinocytosis 

describe passive diffusion

Small molecules up to MW 100-200 (ethanol, ureum) 
Down a conc. gradient 
Influenced by 
• lipophilicity 
• ionisation 
• blood flow: create gradient across membrane 

The degree of transport then is determined primarily by

The degree of transport then is determined primarily by the dissociation constant (pK a) of the substance concerned and the pH in the compartment concerned.

what is pka

defined as the pH at which 50% of the substance is dissociated

is blood flow passive or active

blood flow: create gradient across membrane 

Only the non-ionized form (HA) diffuses across membranes, and blood flow maintains the gradient by removing the substance, enabling continuous passive diffusion

describe 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) 

Describe facilitates diffusion

● 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+) 

how is glucose transported

glucose is transported through facilitated diffusion through a glucose transporter

flavonoid-glycosides can be absorbed via
the glucose transporters in the small intestine

phagocytosis

This is a process where the cell membrane encloses solid particles

pinocytosis:

small amounts of liquid containing solutes (pinocytosis)

cell drinking , almost all cells, ingestion of drops or small aprticles (<1 mm)

draw graph for uptake kinetics

red line is passive

blue line theres plateau, enzymes become saturated

what are the main exposure routes toxic subtances are taken up by

1. the respiratory system,
2. the digestive or gastrointestinal tract,
3. the skin,
4. alternative routes including the gills (in fish and aquatic invertebrates) or injection of drugs

what is absorption

transfer of chemical from site of exposure into the systemic circulation

what does rate of absorption depend on

-          Conc chemical at absorbing surface

-          Area of exposed site

-          Characteristics of epithelial layer where absorption takes place

-          Intensity of sub-epithelial circulation

-          Physiological properties of toxicant

what can happen during transfer of chemical from site of exposure

chemical can get eliminated

where does elimination of chemical during transfer from site of exposure occur usually

Liver

GI mucosa -gastrointestinal mucosa

First pass elimination

reduces toxic effects of chemicals that reach their target sites by the way of systematic circulation.

give example of first pass effect

Lidocaine: most important local anaesthtic

-          Extensive first pass metabolism in liver

-          Useless upon oral dose

Absorption of xenobiotics through the wall of the digestive tract should be considered a

Passive transport

uptake of nutrients taking place through

active transport

what type of compounds are harder to take up through intestinal wall

Generally, highly dissociated substances and hydrophilic
compounds are either hardly taken up through the intestinal wall or not at all, unless the epithelium has
been damaged.

what is the bucco-enteral cycle

• Absorbed → excreted via saliva → reabsorbed in intestine

• Occurs with: lead, silver, mercury, arsenic

what is the entero-hepatic cycle

• Absorbed intestine → liver → bile → intestine → reabsorbed

• Example: DES conjugates

what is the name of barrier function layer in skin

horny layer

What plays biggest role in dermal uptake and what doesnt

The pores little importance in uptake as they give little contribution to skins total surface. Dermal uptake increases with increasing temp through hyperaemia (increased blood flow through skin) and hydration (higher water content of horny layer)

Describe distribution

Toxicants leave blood during distribution phase, enter extracellular phase and may penetrate into cells.

what molecules move readily inside cells

Lipid soluble compounds move readily into cells by diffusion unlike ionised and hydrophilic compounds.

what is distribtuion mainly controlled by

Distribution mainly determined by blood circulation.

what are the main routes of distribution

• cappilaries

• intracellular space

• fenestrae

what factors affect distribution speed

• blood flow

• diffusion rate

• tissue affinity

what can cause uneven distribution

substances bind to proteins/tissue causing uneven distribution an longer residence time.

give name of plasma protein

Albumin

what does albumin do

• Plasma proteins (Albumin) : It can bind to xenobiotics. reversible binding. In bound form not avialble for distrubution or filtration by kindey. Protects individual to some extent against toxic effects.

what are the 2 organs with high capacity for binding and accumulation

Liver and Kidney

give an example of something that binds in liver and kidney

metallothionein binds cadmium and other metals in the liver and the kindey.

Which substances accumulate in fatty tissue

• Substances with high octanol/water partition coefficient ( lipholicic PCBs, PBBs, dioxins, DDT) often accumulate in fatty tissue.

whats another place toxicants can accumulate in

bones - long term storage sites

what is it called when toxicants accumulate in bones

skeltal fluorosis

F- replaces OH- in bones

excessive tea drinking

what is the specific blood brain barrier

CNS  (central nervous system)- site less permeable than other sites

•  no fenestrae 

• less permeable due to tighter junctions 

•  Low protein content of interstitial fluid 

• mainly active transport 

•  not fully developed at birth: toxicity for newborn.

these features provide some protection against distribution of toxic chemicals to the CNS and thus against toxcicity.

describe the placental barrier

-Not really a barrier 
- toxic agents: pass by passive diffusion 
alcohol easily crosses the placental barrier 

what are the routes of excretion

kidney: urinary excretion

liver: via bile, fecal excretion

lung: exhalation

other routes: mother milk, saliva, sweat