BIOPHARMACEUTICS

Adapted by : S. Campbell-Elliott M. Pharm. Sc.

Prepared by : A.S. Adebayo, Ph.D.

&
M. A Williams. M.S.

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General Overview/Definitions
 Biopharmaceutics - concerned with relationship between
the physicochemical properties of a drug in a dosage form
and observed therapeutic response after administration.
 Biologic response
 Expressed as alteration of biologic process existing
before drug was administered
 Magnitude is related to drug concentration achieved at
receptor site.
 The observed effect of drug from a dosage form =
inherent pharmacological activity of the drug + its
ability to reach the receptor site in appropriate
concentration
 Onset, intensity and duration of therapeutic effect drugs
depend on biological + dosage form factors
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General Overview/Definitions
(Cont.)
 These factors are important for: attaining desired
drug conc. in the body + sustaining
concentrations for desired length of time + drug
removal after desired effect is attained.

 Biopharmaceutics affords a basic understanding

of the processes of drug absorption, distribution
and elimination + potential effects of dosage form
on these processes that can be applied to
optimize therapeutic outcome of a patient.

 Dosage form of a drug exerts its major influence

on the absorption process
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 Biopharmaceutics
Biopharmaceutics - “the effects of dosage
form and route of administration on the
biological effect of a drug”
 -study of factors influencing the presence of drug
at the site of absorption and the transfer of the
dissolved drug across biomembrane(s) into the
systemic circulation.
 Biopharmaceutical methods: application of
knowledge of drug release and transport across
biomembranes to obtain/predict therapeutic
effect from a product on administration to a
patient.

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Factors Influencing the time course
of a drug in plasma
 The physical/chemical properties of the drug
 Type of dosage form of the drug
 Composition and method of manufacture of the dosage
form
 The size of the dose and frequency of administration of the
dosage form
 Site of absorption of the administered drug
 Co-administration of other drugs
 Type of food taken by the patient
 The disease state of the patient that may affect drug
absorption, distribution and elimination of the drug
 The age of the patient.
 The genetic composition of the patient

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Bioavailability: rate & extent
 Bioavailability - transfer of drug from its
site of administration into the body
system; manifested by appearance in
general circulation.

 Characterized by rate of transfer and the

total amount (extent) transferred

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Factors Influencing Drug Absorption

 Can be categorized into 3 factors:

 Physiological factors

- Nature of the cell membrane

 Semi-permeable: Permits only water, selected
small molecules and lipid-soluble molecules.
 Highly charged molecules and large molecules
e.g. proteins and protein-bound drug will not
cross.

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Factors Influencing Drug Absorption
 Physicochemical factors

 Surface area of the drug

 Crystal or amorphous form
 Salt form
 State of hydration
 Solubility

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Factors Influencing Drug Absorption
 Dosage form factors
- The route of administration
- The inert ingredients e.g. diluents,
binders, disintegrants, suspending
agents, coating agent, etc.
-Type of dosage form e.g. tablet, capsule,
solution,suspension, suppository, etc.

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Schematic illustration of the steps involved in the appearance of intact drug in systemic
circulation following oral administration of a tablet
STOMACH (Gastric content. SMALL INTESTINE (Intestinal
pH 1-3) cont. pH 5-7)

Tablet Tablet

Disintegration
Granules Granules

Deaggregation
Fine Fine
particles particles

Dissolution Dissolution

Drug in Drug in
solution solution

Absorption
Intestinal metabolism

Intact drug
Hepatic
Metabolism Metabolites
Liver
(1st Pass Effect)

Intact Drug in systemic

Circulation
Urine
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Pharmacologic effect
Rate Limiting Steps of Absorption
Nature of Drug Rate Limiting Step

Poor aqueous Rate of dissolution in gastrointestinal fluid

solubility
High aqueous Rate at which drug crosses membrane of the GIT
solubility
Dosage Design Rate of release from the dosage form

Other factors Rate of gastric emptying into small intestine

Rate at which drug is metabolized by the enzymes in the

intestinal mucosal cells en route into mesenteric blood
vessels
06/27/10 Rate of metabolism of drug during its initial passage through
11

the liver (i.e. First-pass effect).

 Physiological Factors
Affecting Oral Absorption

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 Fate of a Drug Product

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Simplified Model of Membrane

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 Davson-Danielli Model

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 Examples of Biomembranes

 Blood-brain barrier
 Has effectively no pores to prevent many polar
materials (often toxic ) from entering the brain.
 Smaller lipid or lipid soluble materials, such as diethyl
ether, halothane (used as general anesthetics) can
easily enter the brain.

 Renal tubules
 Relatively non-porous; lipid compounds or non-ionized
species (dependent of pH and pKa) are reabsorbed.

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 Examples of Biomembranes
(cont’d)
 Blood capillaries and renal glomerular
membranes

 Quite porous, allowing non-polar and polar molecules

(up to a fairly large size, just below that of albumin,
(M.Wt. 69,000) to pass through.
 Especially useful in the kidneys as it allows for excretion
of polar (drug and waste compounds) substances.

 Placental barrier – Research!!!

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Structure of the Gastro-intestinal Tract

 The GIT consists of 4 anatomical regions:

 Oesophagus
 Stomach
 Small intestine
 Large intestine (colon).

 The luminal surface varies throughout the tract – suited for

function

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 Physiology of the G.I.T.
 Hollow muscular tube composed of 4 concentric
layers of tissues:
 Mucosa (mucous membrane)
 Sub-mucosa
 Muscularis externa
 Serosa (outermost layer).

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 Physiology of the GIT :
Structure of the wall
 Serosa –
epithelium +
connective tissue
 Muscularis externa
– moves GI
contents
 Submucosa
 Secretory tissue
 Rich supply of
blood and
lymphatic vessels
 Network of nerve
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 Physiology of the G.I.T. :
The Mucosa
 Mucosa is most important for drug absorption.
- It contains the cellular membrane through which a drug
must pass in order to reach the blood (or lymph).

 The mucosa is itself made of 3 layers:

 Lining epithelium
 Lamina propria
 Muscularis mucosa

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 Physiology of the G.I.T.:
The Mucous Layer
 The gastrointestinal epithelium is covered by a layer of
mucus.

 Mucuous acts as a protective layer and a mechanical

barrier.
 It has a large water component (95%).

 It also contains large glycoproteins (mucin)

 The mucus layer ranges in thickness from 5 µm to 500 µm

along the length of the gastrointestinal tract, with average
valves of around 80 µm.

 The layer is thought to be continuous in the stomach and

duodenum
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 Physiology of the GIT:
The Oesophagus
 Links the oral cavity with the stomach.
 Composed of a thick muscular layer, approx.
250mm long and 20mm diameter.
 Epithelial cell function is mainly protective:
 simple mucus glands secret mucus into the
narrow lumen to lubricate food and protect the
lower part of the oesophagus from gastric acid.
 The pH of the oesophageal lumen is usually
between 5 and 6.
 The oesophageal transit of dosage form is
approx. 10-14 seconds

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 Physiology of the GIT:
The Stomach
 Most dilated part of the gastrointestinal tract.

 Situated between the lower end of the

oesophagus and the small intestine.

 Opening to the duodenum is controlled by the

pyloric sphincter.

 Capacity of approx. 1.5L

 Very little drug absorption occurs in the stomach

due to relatively small surface area (compared to
small intestines).
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 Physiology of the GIT:
The Stomach (cont’d)
 Gastric secretions:
 Acid secreted by parietal cells - maintains the pH of the
stomach between 1 and 3.5 in fasted state.

 Hormone gastrin - potent stimulator of gastric acid

production.

 Pepsin - secreted by peptic cells in the form of its

precursor, pepsinogen; peptidase which break down
proteins to peptides at low pH; above pH 5 pepsin is
denatured.

 Mucus - secreted by the surface mucosal cells and lines

the gastric mucosa; protects gastric mucosa from auto
digestion by the pepsin-acid combination.
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 Physiology of the GIT:
The Small Intestine
 Longest (4-5m) and most convoluted part of the GIT,
extending from the pyloric sphincter (of stomach) to the
ileo-caecal junction where it joins the large intestines.

 Main functions:
Digestion:
Process of enzymic degradation; begins in the stomach
and completed in the small intestine.

Absorption:
Small intestine is the region where most nutrients and
other materials are absorbed.

 Divided into the duodenum (200-300mm long), the

jejunum (≈2m long) and the ileum (≈3m in length).
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 Physiology of the GIT:
The Small Intestine (cont’d)
The luminal pH of the small intestine increases to 6 -7.5 due
to :
 Brunner’s glands:
 Located in the duodenum
 responsible for the secretion of bicarbonate which neutralizes
the acid emptied from the stomach.

 Intestinal cells:
 present throughout the small intestine
 secrete mucus and enzymes, such as hydrolases and proteases

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 Physiology of the GIT:
The Small Intestine (cont’d)
The following structures are responsible for the very large
surface area of the small intestine.

 Folds of Kerckring:
 Submucosal folds extending circularly most of the way around the
intestine; well developed in the duodenum and jejunum

 Villi:
 described as finger–like projections into the lumen
 (approx. 0.5 - 1.5mm in length and 0.1mm in diameter).
 Well perfused

 Microvilli:
 approximately 600-1000 brush-like structures (1 µm in length and 0.1
µm in width) cover each villus,
 provides the largest increase in the surface area.

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 Increase in Surface Surface Area
Structure (relative to cylinder) sq cm
simple 1
cylinder
3,300

Folds of 3 10,000
Kerckring

30 100,000
Villi

600 2,000,000
Microvilli

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 Physiology of the GIT:
The Colon
 Terminal portion of GIT.

 Unlike the small intestine, has no specialized villi.

 However, the surface area is increased by the following

 microvilli of the absorptive epithelial cells
 presence of crypts
 irregular folded mucosae serve to increase the surface area of the
colon by 10-15 times.

Main functions are:

 The absorption of sodium and chloride ions and water from the
lumen in exchange for bicarbonate and potassium ions.
 Significant homeostatic role in the body.
 Storage and compaction of faeces.

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 Physiology of the GIT:
The Colon (cont’d)
 Colonized by a large number and variety of bacteria (about
1012 per gram of contents).

 Bacterial mass is capable of several metabolic reaction,

including hydrolysis of fatty acids, reduction of inactive
conjugated drugs to their active form.

 They degrade polysaccharide to produce short- chain fatty

acids (acetic, proprionic butyric acids); generation of
gases hydrogen, carbon dioxide and methane (lowers
luminal pH to 6 - 6.5)

 This increases to around 7-7.5. toward the distal parts of

the colon.

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