ADME

Question 1

Pharmacokinetic profile

Answer 1

What body does to the compound

Question 2

Pharmacodynamics

Answer 2

What a compound does to the body

Question 3

Efficacy

Answer 3

Capacity of a compound to produce a desired biological endpoint

Question 4

Potency

Answer 4

The amount of compound required to produce an effect of a given intensity

Question 5

Absorbtion

Answer 5

-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

Question 6

Distribution

Answer 6

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

Question 7

Metabolism

Answer 7

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

Question 8

Excretion

Answer 8

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

Question 9

In vitro techniques to study ADME properties of compounds

Answer 9

High throughput robotics
sophisticated detection systems
-specialised cell lines
advanced molecular modeling software have been developed to predict ADME properties

Question 10

In Vivo techniques to study ADME

Answer 10

-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

Question 11

effect of using in vitro and in vivo to study PK properties

Answer 11

Clinical failures due to poor PK properties between 1991 and 2000 decreased from 39% to 8%

Question 12

Pharmacokinetic profile of a compound

Answer 12

1.Clearance
2.Volume of distribution
3.Half-life
4.Bioavailibility

Question 13

Clearance

Answer 13

Describes how efficiently the body removes a compound from the systemic circulation

Question 14

Volume of distribution

Answer 14

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

Question 15

Half-life

Answer 15

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

Question 16

Bioavalibility

Answer 16

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

Question 17

Determination of oral pharmacokinetic profile of a given drug

Answer 17

1. Its absorption in the gastrointestinal tract
2. Its distribution through systemic circulation, extracellular fluids and tissues
3. The rate at which it is metabolised
4. The rate at which it is excreted by the kidneys

Question 18

Transporters that play a major role in chemotherapy-induced drug resistance in cancer cells

Answer 18

-Pgp ( a member of the ATP-binding cassette family of transporters)
-Breast cancer resistant protein (BCRP)
-Multidrug resistance protein 2 (MDR2)

Question 19

Factors affecting distribution

Answer 19

-Permeability
-Transporters
-Plasma Binding proteins

Question 20

Transporter effect distribution

Answer 20

-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

Question 21

Plasma binding protein effect on distribution

Answer 21

-Human serum albumin (HSA) and alpha 1-acid glycoprotein (AGP)
-Transport naturally occuring compounds through the body
-Binds with xenobiotics

Question 22

Elimination Pathways

Answer 22

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

Question 23

First pass metabolism

Answer 23

First time compound passes through liver
Liver is systemic circulation

Question 24

Prodrugs

Answer 24

It is a medication or compound that, after administration, is metabolised (converted within the body) into a pharmacologically active drug

Question 25

E.Prodrug

Answer 25

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

Question 26

Phase 1 of metabolism

Answer 26

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

Question 27

monooxygenases

Answer 27

enzymes that add oxygen atom

Question 28

Phase 2 metabolism

Answer 28

Takes advantage of the presence of attachment such as hydroxyl groups, by adding polar groups to molecules such as glucuronic acid or glutathione

Question 29

highly metabolised drugs

Answer 29

Compounds that are highly metabolised are typically removed from the systemic circulation before they are able to exert an impact on a biological system

Question 30

DDI

Answer 30

drug-drug interaction- impacts metabolic stability

Question 31

Most important methods of excretion

Answer 31

Excretion into urine by the kidneys and deposition into bile fluids by the liver

Question 32

Renal excretion

Answer 32

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

Question 33

Liver excretion

Answer 33

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

Question 34

What determines clearance

Answer 34

-Liver metabolism
-Excretion into the urine
-Removal of compound into bile fluids
-Any other process that removes the compund from systemic circulation

Question 35

Single compartment model

Answer 35

Concentration of a drug in the plasma can be used as a tool for determining the PK properties of a compound

Question 36

upper limit of clearance

Answer 36

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

Question 37

Clearance equation

Answer 37

CL=Q*Er

Question 38

Extraction ratio

Answer 38

It indicates the portion of a compound that is removed from a particular organ each time blood passes through the organ in question

Question 39

what is in vivo half life dependant on

Answer 39

t=0.693*(Vd/Cl)
Clearance and volume of distribution (Vd/Cl)

Question 40

how are in vivo pharmacokinetic studies performed

Answer 40

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

Question 41

how to increase solubility

Answer 41

-Molecular weight: smaller molecule
-Polarity: adding polar groups, increasing no. of hydrogem bond donors and acceptors or by adding ionisble groups
-simple isoteric replacement

Question 42

permeability

Answer 42

Passing through cellular barriers that seperate the gastrointestinal tract from systemic circulation
-Differences in membrane composition, junction tightness, transporter activity