1 Oral drug absorption Dr Mohammad Issa Saleh

2 Oral drug absorption The oral route of administration is the most common and popular route of drug dosing The oral dosage form must be designed to account for extreme pH ranges, the presence or absence of food, degradative enzymes, varying drug permeability in the different regions of the intestine, and motility of the gastrointestinal tract

3 Anatomic and Physiologic Considerations

4 Drugs administered orally pass through various parts of the enteral canal, including the oral cavity, esophagus, and various parts of the gastrointestinal tract Residues eventually exit the body The total transit time, including gastric emptying, small intestinal transit, and colonic transit, ranges from 0.4 to 5 days The most important site for drug absorption is the small intestine. Small intestine transit time (SITT) ranges from 3 to 4 hours for most healthy subjects

5 Anatomic and Physiologic Considerations If absorption is not completed by the time a drug leaves the small intestine, absorption may be erratic or incomplete The small intestine is normally filled with digestive juices and liquids, keeping the lumen contents fluid In contrast, the fluid in the colon is reabsorbed, and the lumenal content in the colon is either semisolid or solid, making further drug dissolution erratic and difficult The lack of the solubilizing effect of the chyme and digestive fluid contributes to a less favorable environment for drug absorption in the colon

6 Oral drug absorption Oral Cavity Esophagus Stomach Small intestine: –Duodenum –Jejunum –Ileum Colon Rectum

7 Oral Cavity Saliva is the main secretion of the oral cavity, and it has a pH of about 7 Saliva contains ptyalin (salivary amylase), which digests starches Mucin, a glycoprotein that lubricates food, is also secreted and may interact with drugs About 1500 mL of saliva is secreted per day

8 Esophagus The esophagus connects the pharynx and the cardiac orifice of the stomach The pH of the fluids in the esophagus is between 5 and 6 The lower part of the esophagus ends with the esophageal sphincter, which prevents acid reflux from the stomach Tablets or capsules may lodge in this area, causing local irritation Very little drug dissolution occurs in the esophagus

9 Stomach The fasting pH of the stomach is about 2 to 6. In the presence of food, the stomach pH is about 1.5 to 2, due to hydrochloric acid secreted by parietal cells Gastrin is released from G cells, mainly in the antral mucosa and also in the duodenum Gastrin release is regulated by stomach distention (swelling) and the presence of peptides and amino acids

10 Stomach Hydrochloric acid is produced by the parietal cells in response to histamine, gastrin or acetylcholine stimulation Basic drugs are solubilized rapidly in the presence of stomach acid Mixing is intense and pressurized in the antral part of the stomach, a process of breaking down large food particles described as antral milling.

11 Duodenum A common duct from the pancreas and the gallbladder enters into the duodenum The duodenal pH is about 6 to 6.5, because of the presence of bicarbonate that neutralizes the acidic chyme emptied from the stomach The pH is optimum for enzymatic digestion of protein and peptide food Pancreatic juice containing enzymes is secreted into the duodenum from the bile duct

12 Duodenum Trypsin, chymotrypsin, and carboxypeptidase are involved in the hydrolysis of proteins into amino acids Amylase is involved in the digestion of carbohydrates Pancreatic lipase secretion hydrolyzes fats into fatty acid The complex fluid medium in the duodenum helps to dissolve many drugs with limited aqueous solubility. The duodenum is a site where many ester prodrugs are hydrolyzed during absorption The presence of proteolytic enzymes also makes many protein drugs unstable in the duodenum, preventing adequate absorption.

13 Jejunum The jejunum is the middle portion of the small intestine, between the duodenum and the ileum Digestion of protein and carbohydrates continues after addition of pancreatic juice and bile in the duodenum This portion of the small intestine generally has fewer contractions than the duodenum

14 Ileum The ileum is the terminal part of the small intestine This site has fewer contractions than the duodenum The pH is about 7, with the distal part as high as 8 Due to the presence of bicarbonate secretion, acid drugs will dissolve. Bile secretion helps to dissolve fats and hydrophobic drugs The ileocecal valve separates the small intestine from the colon

15 Colon The colon lacks villi and has limited drug absorption also, because of the more viscous and semisolid nature of the lumen contents The colon is lined with mucin that functions as lubricant and protectant The pH in this region is 5.5 to 7 A few drugs, such as theophylline and metoprolol, are absorbed in this region Drugs that are absorbed well in this region are good candidates for an oral sustained-release dosage form

16 Colon The colon contains both aerobic and anaerobic microorganisms that may metabolize some drugs For example, L-dopa and lactulose are metabolized by enteric bacteria

17 Rectum The rectum is about 15 cm long The rectum has a small amount of fluid (approximately 2 mL) with a pH about 7 The rectum is perfused by the superior, middle, and inferior hemorrhoidal veins The inferior hemorrhoidal vein (closest to the anal sphincter) and the middle hemorrhoidal vein feed into the vena cava and back to the heart The superior hemorrhoidal vein joins the mesenteric circulation, which feeds into the hepatic portal vein and then to the liver

18 Rectum Drug absorption after rectal administration may be variable, depending on the placement of the suppository or drug solution within the rectum A portion of the drug dose may be absorbed via the lower hemorrhoidal veins, from which the drug feeds directly into the systemic circulation; some drugs may be absorbed via the superior hemorrhoidal vein, which feeds into the mesenteric veins to the hepatic portal vein to the liver, and be metabolized before systemic absorption

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Physiologic Factors Affecting Oral Bioavailability The rate and extent of drug absorption from the stomach depends to a great extent on the pH of the gastric contents and the pKa of the drug The pH and pKa relationship regulates the degree of dissolution and ionization of a drug that is administered in solid form This relationship also controls the extent to which a drug precipitates out of solution 20

Physiologic Factors Affecting Oral Bioavailability The pH of the stomach contents is strongly acidic and typically ranges between 1 and 3 for fasted and fed states, respectively; Many drugs are prone to chemical degradation in the highly acidic gastric environment 21

Physiologic Factors Affecting Oral Bioavailability Absorption from the stomach is also impaired by the thick layer of mucus on the gastric lining, which rends to slow the passage of drug across the membranc As a result, drug absorption from the stomach is generally low Most drugs are absorbed more quickly and effectively from the small intestine than from the stomach 22

Physiologic Factors Affecting Oral Bioavailability The small intestine serves as a primary absorption site for drugs because of its extraordinarily large surface area and favorable membrane permeability Consequently, intestinal transit time significantly affects drug absorption, particularly of drugs that exhibit poor dissolution or are absorbed by active transport 23

Physiologic Factors Affecting Oral Bioavailability The surface area available for absorption in the small intestine is greatly multiplied by the presence of fingerlike projections called villi and microvilli Also, the pH range in the small intestine is much wider than that in the stomach The pH in the proximal portion of the small intestine is roughly 5, whereas in the distal region it is roughly 7 to 8 24

Three mechanisms for increasing surface area of the small intestine. The increase in surface area is due to folds of Kerkring, villi, and microvilli 25

Physiologic Factors Affecting Oral Bioavailability This wider pH range makes the environment favorable for absorption of a larger number of drugs Thee large intestine, which includes the colon and rectum, is a major site for water resorption and production of feces The large intestine has a much smaller surface area than the small intestine and is not a favorable site for drug absorption. 26

Physiologic Factors Affecting Oral Bioavailability A drug's stability is a function of the surrounding pH Many drugs are unstable in the environment of the stomach and will degrade when exposed to an acidic pH A drug may undergo degradation in the GIT or biotransformation in the intestinal mucosa or in the liver before reaching the systemic circulation 27

Physiologic Factors Affecting Oral Bioavailability In addition, enzymes such as pepsin, chymotrypsin, and trypsin are also present in the GIT These enzymes are responsible for the degradation and breakdown of proteins and peprides Cytochrome P-450 3A4, which is expressed in the intestinal mucosa, is a member of the crochrome P-450 oxidase system 28

Physiologic Factors Affecting Oral Bioavailability Cytochrome P-450 3A4 is responsible for the biotransformation of a number of drugs, including cyclosporin, midazolam, and tacrolimus, during absorption across the intestinal mucosa Another major factor that limits drug absorption is the efflux drug transporter P- glycoprotein 29

Physiologic Factors Affecting Oral Bioavailability This glycoprotein is localized in the apical membrane of the epithelial cells in the intestinal mucosa Drugs that are absorbed from the GIT are transported to the liver via the hepatic portal vein These drugs may undergo some metabolism by the enzymes that are present in the liver 30

Physiologic Factors Affecting Oral Bioavailability This metabolism of a drug in the liver before the drug reaches the systemic circulation is referred to as first-pass hepatic metabolism In some instances virtually the entire amount of a drug is metabolized and inactivated by this first-pass metabolism (cg, nitroglycerin) 31

First-pass hepatic metabolism 32

Not included

Informal HW 34

Informal HW In the previous figure, the major site of drug absorption is the stomach (true or false) Explain the association between Cmax and gastric emptying rate Explain the association between Tmax and gastric emptying rate A shorter gastric emptying half life implies a faster gastric emptying rate (true of false) 35