Name 4 processes that influence drug disposition?
How do most drugs leave the body?
In the urine.
In what form are they excreted?
Either as unchanged (ie. highly charged) compounds
Chemically transformed compounds rendered more polar by metabolism
Drugs can also be excreted by the bile
Drugs are xenobiotics act to?
Convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney.
Converted drugs to metabolities that are usually pharmacological less active than parent compound
Drugs metabolities may also?
Be converted from inactive prodrugs to active compounds or gain activity.
Have unchanged activity
Possess a different action.
What is the main organ for drug metabolism?
What other organs also has an effect?
Additionally, the GI tract, lungs and plasma
Phase 1 of the drug metabolism?
- Makes drug more polar, adds a chemically reactive group permitting conjugation.
- Drug presented to the liver and enters hepatic cells.
- Metabolism starts: oxidation, reducation & hydrolysis.
- Provides the start point for phase 2
- Catabolic- break down molecules
- Provides the start point for phase 2
Phase 2 of drug metabolism?
- Adds on endogeneous compound increasing polarity.
- Metabolism: conjugation
- Drugs is excreted by kidneys
- Anabolic- synthesis of complex molecules
When can you skip phase 1?
If parent compound already has a handle (permitting conjugation)
When can phase 1 and 2 be skipped?
If parent compound is already polar
Where is haem protein located?
In the endoplasmic reticulum of liver hepatocyte
What does the haem proteins mediate?
Oxidation reaction of many lipid soluble drugs
Cytochrome P450 family?
Comprise a superfamily.
Different individuals have overlapping substrate specificites.
How to classify each individual in the cytochrome?
3- gene family
A- gene subfamily
What are the main gene families in the human liver?
The monooxygenase P450 cycle?
Drugs enter cycle as drug substrate.
Molecular oxygen provides two atoms of oxygen.
One atom of oxygen is added to the drug to yield the hydroxyl produce which leaves the cycle (as ROH)
The second atom of oxygen is combined with protons to form water.
What is the cychrome P450 family used for?
To mediate the oxidation reaction (phase 1) of drug metabolism
In the liver
Drug metabolism pathway?
Phase 2 reactions?
Usually results in inactive products.
Largely occurs in the liver.
Involves conjugation of chemically reactive groups
Involves the transfer of glucuranic acid to electron-rich atoms of the substrate.
Many endogenous substrances are subject to this.
Rate of renal excretion?
Differ greatly between drugs.
Products of phase 1/2 metabolism are excreted faster than the parent compound
What are the 3 basic processes involved in renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive reabsorption by diffusion across the tubular epithelium.
Diagram for the basic processes for renal excretion
If a drug is highly polar is it lipopholic of lipophilic
What weight does glomerular filtration occur freely?
Molecular weight of less than 20,000
Provided they are not bound to large plasma proteins.
Bound to plasma proteins?
If a drug molecule is bound it cannot enter the fitration via glomerular filtration.
The equation for the clearance by filtration
CL= GFR x fraction of drug unbound in plasma.
GFR: glomerular filtration rate
What is the normal GFR?
What percentage of renal plasam flow is filtered through the glomerulus?
What is the remaining 80% go?
It is delivered to the peritubular capillaries of the proximal tubule.
What does the epithelial cells of the proximal tubule contain?
Contains 2, independent transporter systems that actively secretes drugs into the lumen of the nephron.
Name the two transport systems that the proximal tubules use?
- Organic anion transporter
- Organic cation transporter
Organic anion transporter?
Handles acidic drugs.
Endogenous acids and the marker for renal plasma flow.
Organic cation transporter
Handles basic drugs
What is more efficient?
Excretio by filtration or by tubular secretion?
Excretion by tubular secretion for drug elimination by the kidneys
The effect of the electrochemical gradient on tubular secretion?
Can concentrate drugs into the tubular fluid against the electrochemical gradient
Tubular secretion is a what process?
Each carrier has a transport maximum for a particular drug.
Why is tubular secretion importatnt for drugs that are highly protein-bound?
As they can secrete them which cannot be done by glomerlar filtration
Free drug concentration reduces secretion (as the drig dissociates from the protein therefore new equilibrium between bound and free drug).
Secretion can totally remove drug-bound by repeatedly producing new equilibrium
Name some drugs that are secreted by OAT?
Name some drugs that are secreted by OCT?
Drugs that share the same transporter system?
Compete with each other for secretion leading to interactions
What percentage of water filtered at glomerulus is reabsorbed?
What makes passive reabsoprtion favourable from drugs?
The concentration of the urine.
Passive reabsorption across the distal tubule by diffusion
Name the 4 factors that infleunce reabsoprtion?
- Lipid solubility
- Urinary flow rate
- Urinary pH
Drugs with high lipid solubility will be extensively reabsorbed and excreted slowly.
Highly polar drugs will be excreted without reabsorption
Urinary flow rate?
Diuresis decrease absorption
Excess production of urine
Degree of ionisation of weak acids and bases
Can stronly influence their reabsorption
Increase excretion of acids
Increase excretion of bases
Used to accelerate the excretion of aspirin in cases of overdosage
As it increases the movement of aspirin to the renal to be excreted