Pharmacokinetics 1: Drug Absorption

Question 1

What is pharmacokinetics?

Answer 1

Branch of pharmacology that deals with what the body does to the drug

Question 2

What are the 4 big questions of pharmacokinetics?

Answer 2

How easily does the drug get into the body?

Where does the drug go once it’s in the body?

Does the drug’s structure change in the body?

How does the drug leave the body?

Question 3

What are the 3 stages of the pharmaceutical phase?

Answer 3

Ingestion

Disintegration and dissolution

Formation of individual drug molecules.

Question 4

What are the steps of the pharmacokinetic phase?

Answer 4

Absorption of the drug -> Metabolism + distribution -> excretion

Question 5

What does ADME stand for?

Answer 5

Absorption Distribution Metabolism and Excretion

Question 6

What are the key routes of drug administration?

Answer 6

Enteral route (most common (80% of medicine) and covers buccal and sublingual routes)

Parenteral route (Drug administration via route other than intestines which bypasses protective effect of liver and GIT)

Question 7

What barriers does the enteral route provide for drugs?

Answer 7

Intestinal wall

Blood vessel walls

Liver

Question 8

What are the 4 methods of parenteral drug administration?

Answer 8

Intramuscular

Subcutaneous

Intravenous

Intradermal

Question 9

Where must parenteral route be used for drug administration?

Answer 9

In clinical environment

Question 10

Where does drug absorption of oral drugs take place?

Answer 10

In theory it should be absorbed along full length of GI tract. However in reality the duodenum is the primary route of absorption. (due to high degree of folding in duodenum and high vascularity)

Question 11

How can drug formulation and absorption be controlled?

Answer 11

The timing and speed of drug release within GI-tract can be controlled through use of bicarbonate, enteric coatings, and delayed release coatings (for release in large intestines).

Question 12

What does starch and bicarbonate do to drug absorption?

Answer 12

It speeds up gas dissolution in gastric contents.

Question 13

What does enteric coating do to drugs?

Answer 13

Preserves them from interacting with the stomach contents.

Question 14

How do drugs get absorbed from the gut?

Answer 14

Transcellular route: influenced by drug size, solubility, and ionisation status. (Through cells)

Paracellular route for small hydrophilic drugs. (between cells)

Newer view has established several classes of membrane drug transporters:

SLC (solute carriers) - they assist passive drug transport.

ABC class transporters use ATP-mediated transport. Some transporters are important for influx and efflux of drugs from the body.

Question 15

What features are common among influx transporters?

Answer 15

Most are bidirectional SLC class members.

Question 16

What features are common among efflux transporters?

Answer 16

Most are unidirectional ABC proteins

Question 17

What efflux transporter is commonly investigated?

Answer 17

P-glycoprotein, this transporter is clinically significant because it returns hundreds of absorbed drugs to the gut lumen.

Question 18

Where is P-glycoprotein commonly expressed besides gut?

Answer 18

Liver canuliculi (important for liver excretion)

Blood-brain barrier (removes drugs from brain)

Proximal tubule

Testes

Question 19

What are the most important rules regarding optimal oral absorption? (Lipinski’s “rule of five”)

Answer 19

1) Molecular mass < 500g/mol
2) Calculated log octanol/water partition coefficient of 5 or less
3) Less than 5 hydrogen bond donors (sum of OH and NH)
4) <10 H-bond acceptors (sum of O and N atoms)

4 rules but each one is a multiple of 5

Question 20

What is the log octanol/water partition coefficient?

Answer 20

A measure of solubility in water vs octanol

Question 21

What constitutes the polar surface area?

Answer 21

Surfaces of drug molecules contain polarised atoms (O or N) and these are counted through computational predictions to estimate predicted intestinal absorption and toxicity/protein + receptor binding

Question 22

What are the measures of drug lipophilicity?

Answer 22

LogP

Polar Surface Area (PSA)

Question 23

What is Egan’s egg?

Answer 23

A graph representation of the limits that a drug’s LogP and PSA can be for optimal absorption and functionality.

Question 24

How does pH affect drug absorption?

Answer 24

Acidic environment favours absorption at the stomach whereas basic pH favours absorption at the duodenum. This is due to ionisation of the drugs. (although most drugs are absorbed at the duodenum regardless)

Question 25

How is efficiency of absorption measured?

Answer 25

It ca be followed by collecting blood samples at defined times after drug dosing.

Drug samples are then prepared for instrumental analysis and then measured via HPLC/MS.

Results are plotted on concentration vs time graphs.

Question 26

What is Cmax? When does this happen?

Answer 26

The maximum concentration that the drug reaches in the blood. This happens at Tmax

Question 27

What does the area under the curve of the drug concentration in blood vs time graph give us?

Answer 27

Total drug exposure

Question 28

What is the MEC?

Answer 28

The minimum effective concentration of the drug

Question 29

Where is the therapeutic window considered to be?

Answer 29

Between the minimum effective concentration and the minimum toxic concentration. (between MEC and MTC)

Question 30

What influences the shape of the drug concentration in blood vs time graph?

Answer 30

Route of administration

Drug formulation strategies (drugs taken via capsule and coated tablet are released different to capsules with coated drug pellets and matrix tablets)

Question 31

How are coated tablets different to normal capsules?

Answer 31

They are released at the same rate but the release happens in a delayed manner

Question 32

How are capsules with coated pellets and matrix tablets different to normal tablets?

Answer 32

They release for a long time and are absorbed at the same rate the entire time

Question 33

What is drug bioavailability?

Answer 33

Simple way of describing how well a drug is absorbed from the site of administration. (it is a fraction where F=1 is a fully absorbed drug)

Question 34

What does drug bioavailability describe and what doesn’t it describe?

Answer 34

It describes extent of drug absorption not rate of absorption.

Question 35

How is bioavailability represented?

Answer 35

With the letter “F” for fraction

Question 36

Where can drug go to decrease its bioavailability?

Answer 36

It can be excreted in faeces, can be metabolised right after being removed from the gut wall, it can be metabolised in the liver.

What ever remains is measured in proportion to what was administered initially and the result is the bioavailability.

Question 37

How is bioavailability measured using area under the curve?

Answer 37

AUCoral/AUCi.v.

Question 38

How can bioavailability of drugs be improved?

Answer 38

Using prodrugs which are hydrophilic groups in molecule that are masked by adding lipophilic substituents to form a pro drug. Prodrug extra groups are cleaved off via enzymes in the body thus making them available.

Question 39

What happens to candesartan before and after adding a prodrug group to it?

Answer 39

Its logD goes from -1 to 5.8

Question 40

What issue can arise from using prodrugs?

Answer 40

They can compete with other drugs for the cleaving receptor resulting in DDI due to lack of activation of some prodrugs.