ADME Flashcards
Pharmacokinetic profile
What body does to the compound
Pharmacodynamics
What a compound does to the body
Efficacy
Capacity of a compound to produce a desired biological endpoint
Potency
The amount of compound required to produce an effect of a given intensity
Absorbtion
-Is the compound:
-readily absorbed in the gastrointestinal (GI) tract
-Distributed broadly throughout the body or does it accumulate in a particular organ or tissue type
-If a drug cannot enter the blood then it is useless
Distribution
is the compound distributed broadly throughout the body or does it accumulate in a particular organ or tissue type
–Drugs that target psychiatric diseases have to be able to cross the blood-brain barrier
-It refers to the reversible transfer of a drug between the various tissues, organs, cells, etc
Metabolism
What is the metabolic fate of the compound, and which enzymes are critical to its metabolism?
-Rapidly metabolised are often removed by the liver before they can influence pharmacological events
Excretion
Is the compound rapidly excreted by the kidneys or is it reabsorbed as it passes through the nephrons.
Excretion by the kidneys removes the compound from the systemic circulation, preventing it from exerting biological activity
In vitro techniques to study ADME properties of compounds
High throughput robotics
sophisticated detection systems
-specialised cell lines
advanced molecular modeling software have been developed to predict ADME properties
In Vivo techniques to study ADME
-Animal pharmacokinetic studies to predict which compounds are capable of delivering potential drug compounds to their biomolecular target and predict drug performance in human populations
effect of using in vitro and in vivo to study PK properties
Clinical failures due to poor PK properties between 1991 and 2000 decreased from 39% to 8%
Pharmacokinetic profile of a compound
1.Clearance
2.Volume of distribution
3.Half-life
4.Bioavailibility
Clearance
Describes how efficiently the body removes a compound from the systemic circulation
Volume of distribution
It is a mathematical term that relates the concentration of the drug in plasma to the total amount of drug in the body as a whole
Half-life
the half life of a compound is the amount of time required to decrease the drug concentration by 50% and is dependant on both clearance and the volume of distribution
Bioavalibility
It refers to the amount of drug that reaches the systemic circulation as compared to an intravenous injection of the same drug
-You lose drug concentration when it passes through the gastro-intestinal tract
Determination of oral pharmacokinetic profile of a given drug
- Its absorption in the gastrointestinal tract
- Its distribution through systemic circulation, extracellular fluids and tissues
- The rate at which it is metabolised
- The rate at which it is excreted by the kidneys
Transporters that play a major role in chemotherapy-induced drug resistance in cancer cells
-Pgp ( a member of the ATP-binding cassette family of transporters)
-Breast cancer resistant protein (BCRP)
-Multidrug resistance protein 2 (MDR2)
Factors affecting distribution
-Permeability
-Transporters
-Plasma Binding proteins
Transporter effect distribution
-work against a concentration gradient
-drugs can be substrates for more than one transporter protein
-Can inhibit action of the drug or protect the brain from Xenobiotics
-Gleevac is a substrate for at least six different transport proteins, each of which influences its tissue distribution
Plasma binding protein effect on distribution
-Human serum albumin (HSA) and alpha 1-acid glycoprotein (AGP)
-Transport naturally occuring compounds through the body
-Binds with xenobiotics
Elimination Pathways
the biological barriers to the entry into the circulatory system of an orally delivered material- the walls of the intestines and the stomach are the first line of defence
-Metabolism and Excretion both play a role
First pass metabolism
First time compound passes through liver
Liver is systemic circulation
Prodrugs
It is a medication or compound that, after administration, is metabolised (converted within the body) into a pharmacologically active drug
E.Prodrug
Tamoxifen acts as a prodrug of active metabolites such as afimoxifene and endoxifen. These metabolites have approximately 30 to 100 times greater affinity for the estrogen receptors compared to tamoxifen
Phase 1 of metabolism
Modify the molecular structure of a compound via processes such as oxidation or dealkylation, adding attachment points such as hydroxyl groups that facilitate excretion by the kidneys
monooxygenases
enzymes that add oxygen atom
Phase 2 metabolism
Takes advantage of the presence of attachment such as hydroxyl groups, by adding polar groups to molecules such as glucuronic acid or glutathione
highly metabolised drugs
Compounds that are highly metabolised are typically removed from the systemic circulation before they are able to exert an impact on a biological system
DDI
drug-drug interaction- impacts metabolic stability
Most important methods of excretion
Excretion into urine by the kidneys and deposition into bile fluids by the liver
Renal excretion
Through nephron- an interlocking system of blood vessel and renal tubes
-it is a function of glomerular filtration, passive diffusion, active secretion and active reabsorbtion
Liver excretion
Compounds and their metabolites can be excreted into the gall bladder along with bile fluid produced by the liver. the gall bladder releases bile fluids into the small intestine, providing an opportunity for reabsorbtion of compounds in the bile fluid. This process is referred to as enterohepatic recirculation
What determines clearance
-Liver metabolism
-Excretion into the urine
-Removal of compound into bile fluids
-Any other process that removes the compund from systemic circulation
Single compartment model
Concentration of a drug in the plasma can be used as a tool for determining the PK properties of a compound
upper limit of clearance
the upper limit of clearance by any organ or tissue is defined by the blood flow into the organ (Q) and the extraction ratio of a compound by that particular organ
Clearance equation
CL=Q*Er
Extraction ratio
It indicates the portion of a compound that is removed from a particular organ each time blood passes through the organ in question
what is in vivo half life dependant on
t=0.693*(Vd/Cl)
Clearance and volume of distribution (Vd/Cl)
how are in vivo pharmacokinetic studies performed
They are performed in multiple species in order to establish dosing levels for efficacy and safety studies of potential lead compounds
Predicting optimal dosing and expected compound exposure cannot be done without proper pharmacokinetic studies
how to increase solubility
-Molecular weight: smaller molecule
-Polarity: adding polar groups, increasing no. of hydrogem bond donors and acceptors or by adding ionisble groups
-simple isoteric replacement
permeability
Passing through cellular barriers that seperate the gastrointestinal tract from systemic circulation
-Differences in membrane composition, junction tightness, transporter activity
