Pharmacokinetics 1: Drug Absorption Flashcards
What is pharmacokinetics?
Branch of pharmacology that deals with what the body does to the drug
What are the 4 big questions of pharmacokinetics?
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?
What are the 3 stages of the pharmaceutical phase?
Ingestion
Disintegration and dissolution
Formation of individual drug molecules.
What are the steps of the pharmacokinetic phase?
Absorption of the drug -> Metabolism + distribution -> excretion
What does ADME stand for?
Absorption Distribution Metabolism and Excretion
What are the key routes of drug administration?
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)
What barriers does the enteral route provide for drugs?
Intestinal wall
Blood vessel walls
Liver
What are the 4 methods of parenteral drug administration?
Intramuscular
Subcutaneous
Intravenous
Intradermal
Where must parenteral route be used for drug administration?
In clinical environment
Where does drug absorption of oral drugs take place?
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)
How can drug formulation and absorption be controlled?
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).
What does starch and bicarbonate do to drug absorption?
It speeds up gas dissolution in gastric contents.
What does enteric coating do to drugs?
Preserves them from interacting with the stomach contents.
How do drugs get absorbed from the gut?
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.
What features are common among influx transporters?
Most are bidirectional SLC class members.
What features are common among efflux transporters?
Most are unidirectional ABC proteins
What efflux transporter is commonly investigated?
P-glycoprotein, this transporter is clinically significant because it returns hundreds of absorbed drugs to the gut lumen.
Where is P-glycoprotein commonly expressed besides gut?
Liver canuliculi (important for liver excretion)
Blood-brain barrier (removes drugs from brain)
Proximal tubule
Testes
What are the most important rules regarding optimal oral absorption? (Lipinski’s “rule of five”)
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
What is the log octanol/water partition coefficient?
A measure of solubility in water vs octanol
What constitutes the polar surface area?
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
What are the measures of drug lipophilicity?
LogP
Polar Surface Area (PSA)
What is Egan’s egg?
A graph representation of the limits that a drug’s LogP and PSA can be for optimal absorption and functionality.
How does pH affect drug absorption?
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)
How is efficiency of absorption measured?
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.
What is Cmax? When does this happen?
The maximum concentration that the drug reaches in the blood. This happens at Tmax
What does the area under the curve of the drug concentration in blood vs time graph give us?
Total drug exposure
What is the MEC?
The minimum effective concentration of the drug
Where is the therapeutic window considered to be?
Between the minimum effective concentration and the minimum toxic concentration. (between MEC and MTC)
What influences the shape of the drug concentration in blood vs time graph?
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)
How are coated tablets different to normal capsules?
They are released at the same rate but the release happens in a delayed manner
How are capsules with coated pellets and matrix tablets different to normal tablets?
They release for a long time and are absorbed at the same rate the entire time
What is drug bioavailability?
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)
What does drug bioavailability describe and what doesn’t it describe?
It describes extent of drug absorption not rate of absorption.
How is bioavailability represented?
With the letter “F” for fraction
Where can drug go to decrease its bioavailability?
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.
How is bioavailability measured using area under the curve?
AUCoral/AUCi.v.
How can bioavailability of drugs be improved?
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.
What happens to candesartan before and after adding a prodrug group to it?
Its logD goes from -1 to 5.8
What issue can arise from using prodrugs?
They can compete with other drugs for the cleaving receptor resulting in DDI due to lack of activation of some prodrugs.
