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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