Lecture 2 Absorption Flashcards
What are the 3 consecutive processes of GI absorption?
1) Disintegration and dissolution
2) Passive diffusion and mediated-transport
3) First-pass metabolism
What are the drug factors affecting GI absorption?
1) Release characteristics of dosage form
2) Solubility of drug
3) Ionisation of drug
4) Partition Coefficient of drug
5) Size
What are the physiological factors affecting GI absorption?
1) Gastric Emptying Rate/ Intestinal motility
2) Perfusion of GIT
3) Permeability of gut wall
4) Any form of diseases/ surgeries
What are the three ways for drug to cross the GI membrane?
1) Passive Transcellular (Cross membrane by itself)
2) Facilitated Transcellular (With help of ion channels or transporter)
3) Paracellular (Pass through junctions)
What is Fick’s first law of diffusion?
dQ/dt = Ka*A(GI)
Net rate of transport (Amt/time) = Absorption rate constant (/time) x Amount of drug in GI lumen (Amt)
What is the cut off size for Paracellular transport?
> 350 g/mol
What are the downsides for drugs that are too lipophilic?
1) Poor water solubility
2) Greater propensity to bind to membrane transporters
Where is the main site of absorption in the body?
Small intestine
What are the 4 factors that decide the main site of absorption in the body?
1) Surface area (200m^2)
2) Blood flow (1L/min)
3) Sink Condition
4) More permeable membrane
What is the rate-limiting step in drug absorption?
Gastric Emptying Rate
What are the 3 factors that affect GI motility?
1) Meals (Generally decrease)
2) Physical state of gastric contents (Liquids empties faster than solids)
3) Drugs (Anticholinergic reduces GER, Cholinergic increases GER)
Laying on which side increases GER?
Right side
What would be affected by the rate of absorption?
Tmax and Cmax
What would be affected by the extent of absorption?
Cmax and AUC
What are the different types of transporters and examples?
Uptake (Peptide transporter 1 PepT1, Organic anion-transporting polypeptide 3 OATP3) and Efflux (P-Glycoprotein)
What enzymes can be found on the gut membrane that metabolises drugs?
CYP450 (CYP3A4, CYP2D6)
What are the three fractions to take note of when calculating F?
1) Fa: Fraction that enters intestinal tissues; escaping loss via feces or metabolism from surface enzymes
2) Fg: Fraction reaching portal vein; metabolism within gut wall
3) Fh: Fraction leaving liver; escaping hepatic extraction
F = Fa x Fg x Fh
What happens to Penicillin G when taken orally?
Acidic hydrolysis
What happens to Insulin when taken orally?
Enzymatic hydrolysis
What happens to fexofenadine when taken orally?
Good substrate of efflux transporter and gets shot out
What are the reactions that may reduce absorption?
1) Adsorption (Eg. Charcoal)
2) Conjugation (Eg. Sulfoconjugation, Glucuronidation)
3) Decarboxylation
4) Good substrate efflux transporters
5) Hydrolysis (Acid/ Enzymatic)
6) Oxidation
7) Reduction
The reactions increase water solubility of drug reducing permeation or it sticks to drug and prevents absorption.
What is a suitable site of administration for a large (MW 1449 g/mol), water soluble, ionised, polar base drug like Vancomycin?
IM and SC sites due to the presence of porous capillary membranes (large fenestrations)
Factors affecting absorption from IM and SC sites?
1) Muscle groups
2) Site (IM vs SC)
3) Blood flow
4) Diseases
How do you measure permeability?
[Diffusion Coefficient x Partition Coefficient]/ Thickness
How do you measure absorption rate constant?
[Permeability x Surface Area]/ Volume of GI lumen
Why is the colon not as effective at absorption?
1) Smaller surface area than small intestine
2) Tighter junction than small intestine
3) More efflux transporters found on apical membrane
4) Bacteria affects drugs
Why should you not give drugs with a low F orally?
Drugs with low F are more susceptible to variability where as 0.0001 change to 0.001 is equivalent to a 10 fold increase which may severely affect the AUC and effect of the drug
True/False: Inter-individual variability is due to polymorphism of transporters
True
Why higher perfusion rate equals to higher Cmax?
Because absorption rate is perfusion rate limited. If perfusion rate increases, rate of absorption increases; Cmax increases and Tmax decreases
How is Cmax, Tmax and AUC affected when drug is taken with a meal?
All increases
