Physiological%20Factors%20Affecting%20Oral%20Absorption

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Physiological Factors Affecting Oral Absorption

• By
• A. S. Adebayo, Ph.D.

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Objective

• At the end of this topic, we should be able to
• Understand the physiological factors which affect
  the oral absorption of drug products
• Apply the knowledge to optimization of patients
  benefit from administered drug

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Overall picture of drug absorption, distribution,
and elimination
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Davson-Danielli Model
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Simplified Model of Membrane
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Examples of some membrane types
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Blood-brain barrier

• Have effectively no pores in order to prevent
  many polar materials (often toxic materials) from
  entering the brain.
• Smaller lipid materials or lipid soluble
  materials, such as diethyl ether, halothane (used
  as general anesthetics) can easily enter the
  brain.

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Renal tubules

• Relatively non-porous, only lipid compounds or
  non-ionized species (dependent of pH and pKa) are
  reabsorbed.
• Placental barrier find out ??

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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 kidney since it allows
  excretion of polar (drug and waste compounds)
  substances.

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MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES

• The apical cell membrane of the columnar
  absorption cell behaves as a lipoidal membrane,
  interspersed by sub-microscopic water-filled
  channels or pores.
• Water soluble substances of small molecular size
  (radius 0.4 nm) such as urea are absorbed by
  simple diffusion through the water-filled
  channels.

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MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES

• Most drug molecules are too large to pass through
  the aqueous channels.
• The apical cell membrane of the g.i.-blood
  barrier allows the passage of lipid-soluble drugs
  in preference to lipid-insoluble drugs.
• However, most drugs possess both lipophilic and
  hydrophilic entities that enable them to cross
  the barrier by the process of Passive
  Diffusion.

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Passive Diffusion

• Involves the movement of drug molecules from
  region of relatively high to low concentration
  without expenditure of energy.
• Movement continues until equilibrium has been
  reached between both sides of the membrane
• the equilibrium tend to be achieved faster with
  highly permeable (i.e. lipid soluble drugs) and
  when membrane has a large surface area (e.g.
  intestine vs stomach or duodenum).
• The apical cell membrane plays only a passive
  role in the passive diffusion transport process.

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Passive Diffusion (Cont.)

• The main factors determining the rate of drug
  transport are
• Physicochemical properties of the drug i.e.
  particle size, solubility, partition coefficient,
  pH and pKa.
• The nature of the membrane
• The concentration gradient of drugs across the
  membrane.

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Diagrammatic representation of g.i. absorption by
passive diffusion
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Ficks Law of diffusion

• Where dQ/dt rate of appearance of drug in the
  blodd at the site of absorption
• D the effective diffusion coefficient of the
  drug in the gi membrane
• A the surface area of g.i. membrane available
  for absorption by passive diffusion
• k1 the apparent PC of drug between g.i.
  membrane the g.i. fluid.

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Ficks Law of diffusion (Cont.)

• Cg is the concentration of drug in solution in
  the g.i. fluid at the site of absorption
• k2 is the apparent PC of drug between the g.i.
  membrane the blood
• Cb is the concentration of drug in the blood at
  the site of absorption
• h is the thickness of the g.i. membrane.

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Ficks Law of diffusion (Cont.)

• The drug in blood vessel is rapidly cleared away
  and the blood thus serves as a sink for
  absorbed drug as a result of
• Distribution in a large volume of blood i.e.
  systemic circulation
• Distribution into body tissues and other fluids
  of distribution
• Metabolism and excretion
• Protein binding
• Hence, a large concentration gradient is always
  maintained across the g.i. membrane during
  absorption process and this conc. gradient
  becomes the sole driving force behind drug
  absorption by passive diffusion mechanism.

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Specialized Transport Mechanisms

• Active transport
• Facilitated transport

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Active transport

• Substances are transported against their
  concentration gradient (i.e. from low to high
  regions of concentration) across a cell membrane.
  
• It is an energy-consuming process and involves
  active participation of the apical cell membrane
  of the columnar absorption cell.

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Active transport (Cont.)

• Drug molecule or ion forms a complex with a
  carrier which, may be an enzyme or some other
  components of the cell membrane, to form a
  drug-carrier complex.
• This complex then moves across the membrane,
  liberates the drug on the other side and the
  carrier returns to the original state and surface
  to repeat the process.
• As for g.i absorption, transfer occurs only in
  the direction of g.i. lumen to the blood i.e. not
  normally against the conc. gradient, the carrier
  being generally a one-way transport system.

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Active transport (Cont.)

• Several carrier-mediated transport systems exist
  in the small intestine and each is highly
  selective with respect to the structure of
  substances it transports.
• Drugs resembling such substances can be
  transported by the same carrier mechanism.
• E.g. Levodopa resembles tyrosine and
  phenylalanine and is absorbed by the same
  mechanism.
• Active transport proceeds at a rate directly
  proportional to the concentration of the
  absorbable species only at low concentration
• the mechanism becomes saturated at high
  concentrations.

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Illustration of Specialized Transport
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Facilitated transport

• Differs from active transport in that it can not
  transport a substance against its concentration
  gradient
• Does not require energy input.
• Its driving force is the concentration gradient.
• Another transport facilitator is required in
  addition to the carrier molecule.

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Facilitated Transport of Vit. B12
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Receptor-mediated endocytosis

• Process of ligand movement from the extracellular
  space to the inside of the cell by the
  interaction of the ligand with a specific
  cell-surface receptor.
• The receptor binds the ligand at its surface
• Internalizes it by means of coated pits and
  vesicles
• Ultimately releases it into an acidic endosomal
  compartment.

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Receptor-mediated endocytosis
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Pinocytosis

• Substance does not have to be in aqueous solution
  to be absorbed.
• Like phagocytosis, it involves invagination of
  the material by the apical cell membrane of the
  columnar absorption cell lining the g.i.t. to
  form vacuoles containing the material.
• These vacuoles then cross the columnar absorption
  cells.
• It is the main mechanism for the absorption of
  macromolecules such as proteins and
  water-insoluble substances like vit. A, D, E and
  K.

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Convective absorption

• By this mechanism, very small molecules such as
  water, urea and low molecular weight sugars and
  organic electrolytes are able to cross cell
  membranes through aqueous filled channels or
  pores.
• The effective radii of these channels are small
  ( 0.4 nm) such that the mechanism is of little
  significance in the absorption of large,
  water-insoluble drug molecules or ions.
• It is the mechanism involved in the renal
  excretion of drugs and the uptake of drugs into
  the liver.

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Ion-pair transport

• In this mechanism, some ionized drug species
  interact with endogeneous organic ions of
  opposite charge to form absorbable neutral specie
  i.e. an ion-pair.
• The charges are buried in ion pair and the
  complex can now partition into the lipoidal cell
  membrane lining the g.i.t. and be absorbed by
  passive diffusion.
• A suitable mechanism for the absorption of
  quaternary ammonium compounds and tetracyclines
  which are ionized over the entire g.i. pH range.
• Ion pair Organic anions Organic cations
  Neutral molecules (crossing lipoidal membrane by
  passive diffusion.

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Characteristics of G.I physiology
pH Membrane Blood Supply Surface Area Transit Time By-pass liver
BUCCAL approx 7 Thin Good, fast absorption with low dose small Short unless controlled Yes
ESOPHAGUS 5 - 6 Very thick, no absorption - small Short -
STOMACH 1 - 3 decomposition, weak acid unionized Normal good small 30 - 40 minutes, reduced absorption no
DUODENUM 6 - 6.5 bile duct, surfactant properties Normal good very large very short (6" long), window effect no
SMALL INTESTINE 7 8 Normal good very large 10 - 14 ft, 80 cm 2 /cm about 3 hours no
LARGE INTESTINE 5.5 - 7 - good not very large 4 - 5 ft long, up to 24 hr lower colon, rectum yes
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Factors that contribute to the inter-subject
variation in the g.i. pH are

• The general health of the individual
• The presence of localized disease conditions
  (e.g. gastric duodenal ulcers).
• The type and amount of food ingested
• Drug therapy (co-administered drugs)

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Gastric emptying and motility
Dependence of Peak Acetaminophen Plasma
Concentration as a Function of Stomach Emptying
Half-life
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Table 2 - Factors Affecting Gastric Emptying
Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to empty more slowly than liquids
Type of Meal
Fatty food Decrease
Carbohydrate Decrease
Temperature of Food Increase in temperature, increase in emptying rate
Body Position Lying on the left side decreases emptying rate. Standing versus lying (delayed)
Drugs
Anticholinergics (e.g. atropine) Decrease
Narcotic (e.g. morphine) Decrease
Analgesic (e.g. aspirin) Decrease
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Food
Figure 2 - Showing the Effect of Fasting versus
Fed state on Propranolol Concentrations
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Effect of food on absorption of some drugs
Drug/drug group Reported effect Comments
Reduced absorption Reduced absorption Reduced absorption
Atenolol Food decreases the extent of absorption Reduction of about 20 has been reported
Captopril Food decreases the extent of absorption Reduction is 35.5 to 40 and may alter therapeutic effect
Digoxin Absorption delayed but total amount not reduced The lower rate of absorption is not important this chronically administered drug concurrent food intake does not alter the plasma concentration in patients on maintenance therapy
Erythromycin (base stearate) Rate of absorption amount absorbed are reduced Extent of absorption of the base and stearate is reduced in fed state because of acid hydrolysis. Extent of absorption is higher in the fed state for the more stable estolate derivative.
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Effect of food on absorption of some drugs (Cont.)
Increased absorption Increased absorption Increased absorption
Dicumarol Extent of absorption is increase by food
Griseofulvin Absorption increased by concurrent ingestion of fatty meal May be due to dissolution in fat components and absorption through fat uptake mechanisms
Phenytoin Food appears to increase the rate extent of absorption Changes in extent of absorption can be dangerous because of saturable hepatic metabolism.
Propranolol, metoprolol, labetalol hydralazine Absorption greater in fed than in fasted state The low system availability, due to extensive 1st pass metabolism, is increased by 50
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Effect of Intestinal residence time

• Controlled/sustained/prolonged release dosage
  forms as they pass through the entire length of
  the g.i.t.
• Enteric coated dosage forms which release the
  drug only when in the small intestine
• Drugs which dissolve slowly in the intestinal
  fluid
• Drugs which are absorbed by intestinal
  carrier-mediated transport system.

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Drugs affecting gastric emptying rate
Decrease gastric emptying rate Increase gastric emptying rate
Antihistamines Anticholinesterases
Antimuscarenic drugs - Neostigmine
-Atropine -Propantheline - Physostigmine
Ganglion blocking drugs Dopamine antagonists
- Hexamethonium - Domperidone
Opiod analgesics - Metoclopramide
- Diamorphine Iproniazid Reserpine
- Buprenorphine Sodium bicarbonate
- Meptazinol Sumatriptan
- Morphine
Phenothiazines
Sympathomimetics
- Isoprenaline
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END OF PRESENTATION

• QUESTIONS/DISCUSSION