Download In the previous lecture we talked about PGP and we said that it`s

In the previous lecture we talked about PGP and we said that it's ATP
dependent efflux pump and it's responsible for pumping substances out of the
cell.
And we said that if we put caco2 model on transparent matter and make
estimation of mechanism of drug absorption, we can determine weather the
drug is minimized via efflux or not by:
1 – We make culture of caco2 cells
We take one concentration and see the drug absorption through this
concentration.
Conc.1
% drug absorbed from donor to acceptor, not the rate but the
amount of drug transported. If this drug shown us minimum drug absorption
period of time <<after certain
To say that this drug doesn't undergo permeation from donor to acceptor due
to PGP efflux, we must make many experiments:
1 – Make saturation (we put the drug with conc. = 100x rather than 1x).
Here we made saturation of PGP, so we notice that the % of drug transported
increased (significant increase).
2 -put another PGP substrates with the drug (PGP substrate must have
higher affinity to PGP to make competition with the drug) then notice that the
permeation increased (one of the most common PGP substrates is rhodamin
183).
3 – Make inhibition (PGP inhibitor with molecules have high affinity to PGP
but block PGP like Cyclosporine A.
4 – ATP inhibitor (metabolic inhibitor).
5 –if we take one cell, we will notice that this cell has an apical and
basolateral layer
The location of PGP is important (is it on the apical side or basolateral?)
 We said about PGP and BBB, and we said that PGP is located on
the endothelial cell that faces the blood; the molecules enter through
endothelial cell and pumped back into the blood.
 Where PGP are imported?
*In GIT the PGP are located on the apical side of mucosa.
*On the apical membrane, if we put the drug in the apical side and the
donor we will see that the transmission from donor to acceptor is quite
low, because the PGP donor
acceptor is quite low then apical
basolateral is low.
*if a drug is PGP substrate then its apical to basolateral (apical
basolateral) transfer is quite low.
*if there is no PGP, then the drug is transported down its concentration
gradient.
# before making 100x we must put the drug on the basolateral side
(acceptor), it will cross down its conc. Gradient by simple passive
diffusion.
So I the drug transfer (apical
basolateral) = (basolateral
apical)
then the drug is transported by simple passive diffusion (the membrane is
only a barrier). But if there is directionality in transport (transfer from one
side is faster than the other side) that means there is specific carrier in
one membrane more than the other (one side of the membrane).
barrier ‫هذه حكمة في الخاليا حتى تتمكن من ادخال ما تريده من المواد من مكان ألخر ليس بمجرد‬
.carriers ‫نتيجة لوجود ال‬selectivity ‫ولكن حتى يكون هناك‬
 So the presence of efflux pump in apical side makes apical
basolateral transfer of PGP substrate very low, however if e put the drug
at basolateral side it will cross by simple passive diffusion.
If the drug isn't PGP substrate and isn't simple passive diffusion then the
conc. Gradient is the transporter.
To make sure that the drug is PGP substrate, we will put the drug at the
basolateral side and take samples from apical side at different times (if it's
maintained then it's simple passive diffusion but if it's higher then it's PGP
substrate) but WHY? That's because PGP pumps are located on the
apical side (we are talking about GIT absorption). Or we can bring
duodenum-like cells without PGP, if the drug is transported by simple
passive diffusion in the absence of PGP in high quantity but with the
presence of PGP is low then the drug is PGP substrate.
Now we will start with oral absorption of drugs:
**Drug absorption after oral root
*oral root of administration is the most common root
*any dosage form given orally it has to go through extreme PH ranges,
presence of food, presence of enzymes, that's why we have to know
the anatomic and physiologic factors that will affect drug absorption.
*major processes that take place are (secretion (of fluids, buffers,
enzymes and mucous for protection), digestion (breakdown of
nutrients to facilitate the absorption) and absorption).
We will start step wise from putting the drug in the mouth (oral
cavity), then the secretion of saliva (has an average PH around 7 and
it contains enzymes of peptidase, salivary amylase, carbohydrates
digestion enzymes, and there are mucines on the surface of buccal
epithelium for buccal absorption, after oral cavity there is the
esophagus which connects the larynx with the cardiac oryphex of the
stomach (esophagus has PH = 5-6 and little drug dissolution takes
place in it) and in esophagus there is normal motility and peristalsis
that moves whatever is swallowed from pharynx to stomach (motility
usually makes esophageal transient time quite short which means
quite short time to transfer the food from pharynx to stomach 4-16
second).
*in certain cases we may have esophageal dismotility (due to age or
certain disease)
*esophageal transient is dependent on how much water swallowed with
tablet, and on the direction of the body if it's up ward it's faster swallowing.
*usually, when solid dosage form is taken, it must be transported directly to the
stomach, never the less if the patient was bedded and doesn't sit to long time and
takes the solid dosage form with minimal volume of water then the possibility of tablet
to be lodged is high (staying of the tablet in the esophagus longer than expected or
designed) and start dissolution within the esophagus and it might irritate it  so the
bedded patient must be in upright position and take the solid dosage form with glass
full of water to make peristalsis faster then go to sleep if he wants.
Example:::: Alendronate (biphosphonate)(phosomax is the product's name) is
a drug for osteoporosis and these tablets are uncoated tablets and might start
dissolution in esophagus and cause irritation to esophagus, so it has to be taken in
upright position for 30 minutes to minimize lodging
*after esophagus we reach the stomach where emptying occurs. Stomach is
innervated by vagous nerve and there is a local nerve plexus, which fixed under the
control of hormones, mechanoreceptor that are stretch in GI wall, chemoreceptor that
control the secretion and gastric emptying.
*fasting stomach PH is around 6 but in the presence of food the secretions increased
and PH becomes lower and reaches 1.5-2 (stomach acid secretion is controlled by
gastrin and histamine).
*One of the important parameters we will study is stomach (gastric) emptying.
*the major functions of the stomach are food storage, breakdown of food into smaller
particles, very good mixing with acids (then called chime), after the stomach the
emptying to the duodenum takes place where the main function of digestion and
absorption, but nothing reaches the duodenum rather than chime (reduced sizes)
then the food and liquids are emptied by opening the pyloric sphincter into the
duodenum.
*Duodenum: has PH 6-6.5 and this is the optimum PH for enzymes activities, and
here there are pancreatic juices (tripsin, chemotripsin, carboxypeptide, carbohydrates
amylases and pancreatic lipase), here mixing occurs, food digestion and absorption.
*absorption capacity of the duodenum is quite high due to:
1 –numerous surface area for drug absorption (presence of villi and microvilli).
2 –excellent perfusion.
3 –very high level of carrier mediated mechanisms.
*after duodenum we go to the jejunum (the middle portion of the small intestine)
and here the absorption is continued as well as in illium (the distal part of small
intestine) then we reach the colon.
*when reaching the colon we notice that the absorption is quite different,
colon lacks villi so we usually have limited drug absorption (most of
absorption occurs in upper parts of the small intestines)
*contents of colon are viscous and semisolid in nature and this usually limits
absorption of drugs, it's lined with mucine which acts as lubricant affects the
epithelium, PH is alkaline 5.5-7, in colon there are aerobic and anaerobic
microorganisms and these could be responsible for drug metabolism and
drug activation.
*drug that is activated in the colon like sulfa drugs (sulfasalazin)
Sulfasalazine is reduced by bacteria into salicylic acid and aspirin, and it's a
big molecule and doesn't undergo absorption until reaching colon due to the
presence of bacteria.
*so>> colon isn't an ideal site for drug absorption, never the less, drug
activation may take place if drug is activated my microorganisms, and it's
considered as residual area for drug absorption (if the absorption in the
duodenum isn't completed).
** in emptying the food stays seconds in the esophagus and stays at
maximum 2 hours in the stomach then it's emptied into the duodenum, here
contents are more liquidity and have high secretions, drug here is in the
dissolved state and goes to touch the wall of the mucosa then it's absorbed.
*during drug travelling there are movements (circular smooth muscles and
longitudinal) which improve mixing of the drug with secretions and
dissolve the drug inside the lumen of mucosa and absorption occurs.
**for most drug dosage forms that are immediate released are
conventional dosage forms and designed invitro to disintegrate and
dissolve rapidly (stay 1, 2 or 3 hours in the small intestine to be
completely dissolved and absorbed), however, if we have a drug that it's
not completely dissolved during this time or it was sustained released
preparation then it (the drug) will have more time to be absorbed, so the
absorption occurs in the colon of large intestine.
*immediate release: rapid disintegration and dissolution to give very high
peak and give therapeutic response quite high.
*sustained release: designed in the lab to be released slower than normal,
and the purpose of being sustained are:
1 –if the effect is required to be delayed (not prolonged) depending
on the gastric emptying and presence in the duodenum.
2 –if the half life of the drug is short, we will give the patient very
frequent doses (ex: one tablet every 3 hours), so we need to decrease
frequency of doses (here we prepare tablet 150 mg rather than 50 mg for
example and make the tablet sustained release).
*enteric coated ≠ sustained release
Enteric: once they are emptied to the duodenum, dissolution start as
well as disintegration and rapid dissolution and absorption).
**how to make the drug sustained release??
Put it in a polymer, cover with waxy base and put a large dose in one
tablet and make design to release 10 mg for example every hour.
*example: we make the tablet to make release upon 12 hours, so during
12 hours, the drug has to reach the colon (4 hours at least in the colon)
>> (1-2 hours in the stomach, then go to the duodenum and stay 6-7
hours in the small intestine, then go to the colon and stay at least for 4
hours, so that the colon is considered as residual place for drug
absorption for sustained release formulations.
*actually: we can't make a drug to be sustained and stay release to 24
hours in the body, because the travel from mouth to the anus doesn't take
24 hours, but how we said that many drugs can be taken one time in the
month?
These drugs have long half life and stay in the blood (persistent) due to its
very high volume of distribution, very high lipophilicity or the mechanisms
of its elimination are quite slow.
**then we reach the rectum:
The rectum is 15 cm long and ends with anus.
*the presence of fecal matter usually minimize the drug absorption
(small amount of fluid 20 ml) and PH =7
*rectal drug administration usually the target is the colon (last target)
where systemic absorption occurs, but if the drug reaches the rectum
without being dissolved, the absorption may be occurs in the rectum.
*we want absorption rectally with suppositories.
*advantages of rectal drug administration:
Usually, if the absorption happens through the inferior homorhoidal
vein then the drug goes directly to the systemic circulation, but if the
absorption occurs in higher parts then the drug will go to the mortal
cell (liver).
liver ‫ حتى يحدث االمتصاص فيها وال يذهب الدواء الى ال‬rectum ‫اذن نعطي الدواء عن طريق ال‬
*the problem of rectal drug absorption is the presence of fecal matter, so
the contraction makes the chime closer to the mucosa as well as the drug.
*The drug must have opportunity to reach the surface of epithelial cell to
undergo absorption.
**if we go down in the GIT, we have mucous on the epithelial cells in the
stomach and endothelial cells of the duodenum which are barriers, so the
drug that reaches the surface of the cell they have to diffuse across the
mucous then reaches the surface. When the drug reaches the colon the
contents become thicker and drug diffusion across chime becomes
trickier.
**when the drug is put rectally, we have minimum volume of dissolution,
so if we talk about suppositories they have to melt first then partition
occurs between the suppository base and the transmitter, then it has to
cross the thecal blanket, mucous then the cells.
**if we give the patient a drug to clean the rectum then give him a
suppository, then the effect will be higher and faster.
Never the less: rectal drug absorption is said to be erratic (very high
variability between the first second and the second one) due to the thecal
content and the difference in the time.
**drug absorption from GIT:
Passive diffusion is the main mechanism for drug absorption, the optimum
site for absorption is the duodenum due to:
1 –large surface area.
2 –high perfusion.
3 –availability of carrier mediated absorption mechanisms.
**One of the most important factors that influence the drug absorption is
physiologic factors
1 –physiologic factors
2 –physicochemical variables
3 –formulation factors.
** 1) physiologic factors:
a) Gastrointestinal motility:
1) Gastric emptying time (the most important)
2) Intestinal motility
3) GI perfusion
4) GI secretions
5)
**the structure of the elementary tract is: we have hollow tube composed
of many layers, 1) mucosa (epithelial lining), 2) submucosa (mesenteric
blood vessels), 3) muscularis (two layers of smooth muscles, the inner is
circular and the outer is longitudinal and these are responsible for mixing
and peristalsis), 4) serosa (it's connective tissue for lubrication of GIT).

1) Gastric emptying time:
After oral swallowing of dosage form, usually it's
emptied rapidly to the stomach, after reaching the stomach, any
delay in gastric emptying time will delay drug absorption, after
emptying from the stomach to the duodenum (the major site of drug
absorption) any delay in stomach emptying will delay the
appearance of the drug in the systemic circulation, and this usually
will influence the rate and possibly the extent.
(Increasing the stomach emptying time will delay the rate and
reduce the extent if the drug is degraded in acidic PH)
**gastric emptying time has very high intersubject variability:
Cycle of gastric emptying is dependent on the fed-state.
*During fasting (after 8 hours of fasting), the stomach contraction is
in one of 4 stages:
1)30-60 minutes (silent phase): the stomach doesn't make anything
2) Phase 2: from 20-40 minutes, we have irregular contractions
(medium amplitude contraction) and here we have secretion and
contraction.
3) Phase 3: 5-15 minutes, we have regular contraction, mucous
secretions and all contents are emptied from the stomach to the
duodenum (strong waves).
4) phase 4: irregular contraction.
‫مثال‪ :‬اذا كنا كلنا صائمين وال نعرف ما هي ال ‪ phase‬في كل واحد منا‪ ،‬حتى يحدث‬
‫‪ emptying‬من ال ‪ stomach‬الى ال ‪ duodenum‬نحن بحاجة الى ‪ ، contractions‬من‬
‫الممكن ان رنا تكون في ‪ phase 1‬لذلك اذا اخذنا منها ‪ sample‬قبل ان يأتي وقت ال‬
‫‪ emptying‬سنجد ان تركيز الدواء في الدم = ‪ 0‬ولكن اذا كانت هدى في ال ‪ phase 3‬لذلك‬
‫لو أخذنا منها ‪ sample‬بعد ‪ 5-4‬دقاق سنالحظ وجود الدواء في الدم بسرعة‬
‫*حتى لو كنا كلنا صائمون وكنا ‪ standardized‬وأخذنا دواء مع بعض بنفس الثانية وأخذنا‬
‫‪ sample‬بنفس الوقت من كل واحد منا لن تكون ال ‪ plasma conc.‬نفسها الختالف ال‬
‫‪ phase‬بكل واحد‪.‬‬
‫‪Done by: Razan Matar‬‬
‫‪Rely on Allah and study well‬‬
‫‪Best wishes‬‬