1. DRUG ABSORPTION

3. Anatomic and Physiologic
Considerations
 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

4. 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

5. 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. Oral Cavity
 Oral cavity used for buccal/sublingual absorption
of lipid soluble drugs Eg : fentanyl citrate,
nitroglycerin.
 ODT Eg : Ariprazole (antipsychotic) disintegrate
rapidly in the oral cavity in the presence of saliva.
The drug may be administered without water

9. Esophagus
 The esophagus connects the pharynx and 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

11. 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.

12. Stomach
 Fat soluble, acid stable drugs may be absorbed from the stomach
 Stomach emptying is influenced by food content and osmolality.
 Fatty acids, high density foods and mono/di glycerides delay
gastric emptying
 Stomach pH may be increased due to presence of food and certain
drugs such as omeprazole
 Increase in stomach pH may cause a drug interaction with enteric
coated tablets

14. 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
 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

15. Duodenum
 The complex fluid medium in the duodenum helps to dissolve many
drugs with limited aqueous solubility.
 Duodenum is the major site for the passive diffusion of many
drugs. (high S.A, high blood flow)
 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 of
protein drugs

16. 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
 Preferred for in-vivo drug absorption studies.

17. 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

19. Colon
 The colon lacks villi and has limited drug absorption also,
because of the more viscous and semisolid nature of the
lumen contents, lack of large surface area & blood flow.
 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

20. 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
 Crohn’s disease affects colon – increases absorption
of clindamycin, propanolol, decreases absorption of
other drugs.
 Mesalamine targeted to colon to treat the disease.

21. 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 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

22. 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

24. 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

25. 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 membrane
 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

26. 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

27. 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

28. Physiologic Factors Affecting Oral
Bioavailability
 This wider pH range makes the environment
favorable for absorption of a larger number of
drugs
 The increase in surface area is due to folds of
Kerkring, villi, and microvilli

30. Physiologic Factors Affecting Oral
Bioavailability
 The 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.

31. 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

32. 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 cytochrome P-
450 oxidase system

33. 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

34. 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

35. 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 (eg, nitroglycerin)

36. Gastrointestinal Motility
 There are two modes of motility patterns in the stomach and consequently in
the small intestine .
 The digestive (fed) pattern consists of continuous motor activity,
characterized by a constant emptying of chyme from the stomach into the
duodenum.
 The interdigestive (fasted) pattern (commonly called the migrating motor
complex, MMC) is organized into alternating cycles of activity in four phases.
(Rest, Irregural contractions, regular contractions, Irregular contractions)
 Typically, the MMC sequence begins in the stomach or esophagus and
migrates to the distal ileum.

37. Gastrointestinal Motility
 GI motility tends to move the drug through the alimentary canal, so the drug
may not stay at the absorption site.
 For drugs given orally, an anatomic absorption window may exist
within the GI tract in which the drug is efficiently absorbed.
 Drugs contained in a non biodegradable controlled-release dosage form
must be completely released into this absorption window to be absorbed
before the movement of the dosage form into the large bowel.
 The transit time of the drug in the GI tract depends on the
physiochemical and pharmacologic properties of the drug, the type of
dosage form, and various physiologic factors.

38. Gastric Emptying Time
 Anatomically, a swallowed drug rapidly reaches the stomach. Eventually,
the stomach empties its contents into the small intestine.
 Because the duodenum has the greatest capacity for the absorption of
drugs from the GI tract, a delay in the gastric emptying time for the drug to
reach the duodenum will slow the rate and possibly the extent of drug
absorption, thereby prolonging the onset time for the drug.
 Some drugs, such as penicillin, are unstable in acid and decompose if
stomach emptying is delayed.
 Other drugs, such as aspirin, may irritate the gastric mucosa during
prolonged contact.

39. Gastric Emptying Time
 A number of factors affect gastric emptying time.
 Some factors that tend to delay gastric emptying include consumption of
meals high in fat, cold beverages, and anticholinergic drugs.
 Liquids and small particles less than 1 mm are generally not retained in the
stomach.
 These small particles are believed to be emptied due to a slightly higher
basal pressure in the stomach over the duodenum.
 Different constituents of a meal empty from the stomach at different rates.
 Thus, liquids are generally emptied faster than digested solids from the
stomach

40. Gastric Emptying Time
 Therefore the factors that promote gastric emptying tend to increase
the absorption rate of all drugs.
 Slow gastric emptying can delay the onset of effect of drugs such as
analgesics or sedatives in situations requiring prompt clinical
response
 Prompt gastric emptying is important for drugs that are unstable in
stomach fluids because of low pH or enzyme activity.
 For e.g the extent of degradation of penicillin G after oral
administration depends on its residence time in the stomach and on
the pH of the stomach fluids.

41. Gastric Emptying Time
 Factors Influencing Gastric Emptying – Gastric empyting is reduced by :
 1. by fats and fatty acids in the diet,
 2. High concentrations of electrolytes or hydrogen ion
 3. high viscosity or bulk,
 4. Mental depression
 5. Lying on the left side
 6. Diseases such as gastroenteritis, pyloric stenosis, gastroesophageal reflux,
hypothyroidism and luteal phase of menstrual cycle.
 7. Drugs such as atropine, propantheline, amitriptyline, chlorpromazine, aluminium
hydroxide.

42. Gastric Emptying Time
 Gastric empyting is increased by :
 Fasting or hunger
 Alkaline buffer solution
 Anxiety
 Lying on the right side
 Diseases such as hyperthyroidism
 Drugs such as metoclopromide (a dopaminergic blocker used in
nausea and vomitting associated with cancer chemotherapy).

43. Gastric Emptying Time
 Gastric empyting of liquids is much faster than that of food or solid
dosage forms.
 Intact tablets have been observed in the stomach as long as 6 hours
after ingestion of an enteric coated product with a meal.
 Tablets and capsules are commonly swallowed with little or no water
and many patients in bed swallow them.
 Under these conditions a solid dosage form may lodge in the
esophagus and stay there until it disintegrates. This may cause
damage to the esophageal mucosa leading to ulceration and later
perforation.

44. Gastric Emptying Time
 Drugs causing esophageal ulceration includes aspirin, other
NSAIDS, tetracycline, doxycycline, clindamycine, quinidine ,
iron salts.
 Slow esophageal transit also delays drug absorption.
 Patients should be advised that tablets and capsules must be
taken with several swallows (at least 2 ounces) of water or
other beverages, while standing or sitting upright.

45. INTESTINAL TRANSIT TIME
 The motility of the small intestine as indicated by small
bowel transit time also plays a role in drug absorption.
 The mean transit time of unabsorbed food residues or
insoluble granules through the human small intestine
is estimated to be about 4 hours.
 During fasting state – total transit time= 4 -8hrs
 During fed state – total transit time = 8-12 hrs.

46. INTESTINAL TRANSIT TIME
 Short residence in the small intestine has implications for the
design of prolonged release dosage forms
 A product designed to release drug over a 6 –hour period
may demonstrate poor availability if it is rapidly emptied from
the stomach and the drug is poorly absorbed in the large
intestine.
 Propantheline and similar drugs increase small intestine
transit time and metoclopromide accelerates transit through
the small intestine.

47. INTESTINAL TRANSIT TIME
 Delayed intestinal transit is desirable for :
1. Drugs that dissolve / release slowly from their dosage form
2. Dose is higher than solubility eg: chlorthiazide
3. Drugs which are absorbed from specific sites in the intestine
eg : vit B, lithium carbonate etc
4. Drugs which penetrate the intestinal mucosa very slowly eg
: acyclovir.
5. Drugs absorption from the colon is minimal

48. INTESTINAL TRANSIT TIME
 As contents move down the colon its viscosity increases –
limits the design of SR products having short t1/2 values.
 Intestinal transit – influenced by food, drugs, diseases.
 Food – decreases digestive secretions
 Pregnancy retard intestinal transit
 Diarrhoea promotes intestinal transit

49. INTESTINAL TRANSIT TIME
 Metoclopramide – promotes Gastric and Intestinal transit-
enhance absorption of rapidly soluble drugs
 Laxatives - promotes intestinal transit
 Anticholinergics - retard intestinal transit - enhance
absorption of poorly soluble drugs
 Propantheline – shows 100%, 50% and 30% rise in the
absorption of Vit B2, Nitrofurantoin, Hydrochlorothiazide.

52. Double-Peak Phenomenon
 Some drugs, such as ranitidine, cimetidine, and dipyridamole,
after oral administration produce a blood concentration curve
consisting of two peaks.
 This double-peak phenomenon is generally observed after
the administration of a single dose to fasted patients.
 The rationale for the double-peak phenomenon has been
attributed to variability in stomach emptying, variable
intestinal motility, presence of food, enterohepatic recycling,
or failure of a tablet dosage form.

53. Double-Peak Phenomenon
 The double-peak phenomenon observed for cimetidine may be due
to variability in stomach emptying and intestinal flow rates during
the entire absorption process after a single dose.
 For many drugs, very little absorption occurs in the stomach.
 For a drug with high water solubility, dissolution of the drug occurs
in the stomach, and partial emptying of the drug into the duodenum
will result in the first absorption peak.
 A delay in stomach emptying results in a second absorption peak as
the remainder of the dose is emptied into the duodenum.

54. Double-Peak Phenomenon
 In contrast, ranitidine produces a double peak after both oral or
parenteral (IV bolus) administration.
 Ranitidine is apparently concentrated in the bile within the
gallbladder from the general circulation after IV administration.
 When stimulated by food, the gallbladder contracts and bile
containing drug is released into the small intestine.
 The drug is then reabsorbed and recycled (enterohepatic recycling).

55. Double-Peak Phenomenon
 Tablet integrity may also be a factor in the
production of a double-peak phenomenon.
compared a whole tablet or a crushed tablet of
dipyridamole in volunteers and showed that a
tablet that does not disintegrate or incompletely
disintegrates may have delayed gastric emptying,
resulting in a second absorption peak.

56. Effects of food on Drug
Absorption
 Gastrointestinal absorption is favored by an empty stomach.
 One should not give all the drugs on an empty stomach,
some are irritating and should be administered with or after a
meal.
 Food tends to decrease the rate of stomach emptying due to
feedback mechanisms from receptors in the proximal small
intestine and delays the rate of drug absorption.

57. Effects of food on Drug
Absorption
 Foods tend to increase gastric pH which may increase or
decrease the dissolution or chemical degradation of some
drugs.
 Food appears to interact directly with certain drugs either to
enhance or to reduce the extent of absorption.
 Food stimulates hepatic blood flow which may have
implications for the bioavailability of drugs subject to first-pass
hepatic metabolism.

58. Effects of food on Drug
Absorption
 In general, the absorption of drugs taken 30 minutes or more
before not affected by food.
 Food appears to have little effect on drug absorption when
the drug is given 2 hours or more after a meal.
 Food have little effect on drug absorption or may decrease
the rate but not the extent of drug absorption.
 Example of such drugs are digoxin, acetaminophen .

59. Effects of food on Drug
Absorption
 Less important effects are observed with well-
dispersed dosage forms (e.g. solutions,
suspensions, rapidly disintegrating tablets and
capsules) and drugs that are water soluble.

60. Effects of food on Drug
Absorption
 Effect of food on drug absorption may depend on the dosage
form used.
 For example , food delays the absorption of enteric coated
aspirin tablets and digoxin tablets but has no effect on the
absorption of enteric coated aspirin granules and digoxin
elixir.
 Absorption of tetracycline is reduced when these drugs are
taken with milk or milk products because of an interaction
with calcium resulting in a poorly soluble complex.