Absorption from GIT 2 Flashcards
Which state do drugs penetrate into the lipophilic membrane?
Ionised or unionised?
Unionised state
Drug molecules are mostly weak ionisable species (weak acid/base)
What is the pH-partition hypothesis on weak acids?
An acidic drug would penetrate the membrane better from acidic environment, but solubility would be higher in basic environment
What is the pH-partition hypothesis on weak bases?
A basic drug would penetrate the membrane better from more basic environment, nut solubility would be higher in acidic environment
What are the issues of the pH-partition hypothesis?
Absorption of most acidic drugs will be better from small intestines
Due to higher absorption area, perfusion + permeability
What are efflux transporters?
P-glycoprotein is an ATP-dependent transporter that is capable of transportation of an extremely wide variety of drugs OUT of the cell
- one of the most important barriers in intestinal absorption of drugs that are substances to p-glycoprotein
- most p-glycoprotein substrates are lipophilic/amphiphilic
- P-glycoprotein is expressed in the liver, brain, adrenal gland, kidney + intestinal epithelium
- P-glycoprotein is highly expressed by some cancer cells + is responsible for multi-drug resistance of cancer cells
- P-glycoprotein works alongside CYP450 3A4
What is Digoxin used to treat?
What is the effect of induction of P-glycoprotein on absorption of digoxin?
Digoxin is used in treating heart failure, arrhythmias, substrate for P-glycoprotein
Rifampicin = inducer of P-glycoprotein
Pre-treatment wih rifampicin increases efflux process from the enterocyte to the intestinal lume which decreases absorption
How are macromolecules + particles transported into the cell membrane?
Macromolecules + particles are internalised by endocytosis
Pinocytosis for small macromolecules
Phagocytosis for larger particles of 1-2 micrometres
What are peyer’s patches?
M-cells sample particles from GIT for antigens + present them to underlying T + B lymphocytes
The particles are transported to the systemic circulation through the lymphatic system
The amount of material that can be transported via this route is very low
Discuss the pH in the colon
The vast majority of the colonic bacteria is present in the distal GIT.
Discuss the properties of the colonic bacteria
Colonic bacteria are anaerobic + secrete enzymes that are capable of metabolising endogenous + exogenous substances which escape digestion in the upper GIT
What is the primary function of the colon?
Absorption of water + electrolytes
Amount of fluids is low, especially in distal colon
Large intestine (colon) is wider + shorter than the small intestine
How come the surface area of the colon is lower in small intestines but higher than in the stomach?
Colon has microvilli but no villi
There are plicae semilunares (irregular folds) which are along with microvilli to increase the surface area 10-15 times more than a cylinder.
The spectrum of metabolising enzymes are similar in small intestines + colon.
But why is metabolism of the colon lower than in the small intestine ?
Since SA in the colon is lower, the total metabolic activity of the colon is also lower
Drugs absorbed from the colon + upper rectum are absorbed into portal vein + are subjected for hepatic FPM
Drugs absorbed from the lower rectum + anal canal are not going to enter portal vein + therefore avoid hepatic FPM
What type of transporters does the colon + small intestines have?
Colon have no active influx transporters, so carrier-mediated absorption is absent (SI does)
Colon has a higher density of efflux transporters than SI
The long residence time + low enzymatic activity in the colon results in significant absorption from colon for some drugs
What is bioavailability?
What 2 major aspects determine what bioavailability means?
Fraction of administered dose reaching the systemic circulation in unchanged form
2 major aspects:
- rate + extent of absorption across GI wall
- extent of drug metabolism/ breakdown before it reaches systemic circulation
What do we use to predict bioavailability?
Lipinski’s rule + Biopharmaceutics classification system
An orally active drug should have no more than one violation of the following:
- not more than 5 hydrogen bond donors
- not more than 10 hydrogen bond acceptors
- molecular mass less than 500 daltons
- octanol-water partition coefficient not greater than 5
Only 4 rules but all numbers are multiples of 5
