Topic 5: Intestinal Absorption

1
Topic 5 Intestinal Absorption

• Physiology of Huge Absorption Area
• Absorption versus elimination via first-pass
  metabolism and excretion
• Food effects on intestinal motility and
  absorption

2
Structure of Intestine

• Super Structure With Villi and Microvilli.
• Large Absorption Area
• Availability of All Transport Pathways

3
Intestinal Epithelium
4
Intestinal Epithelium
5
Intestinal Epithelium
6
Intestinal Epithelium
7
Intestinal Epithelium
8
Intestinal Epithelium
9
Schematic Epithelium
10
Function of the Intestine

• Absorption
• Excretion
• Immune Functions

11
Absorption Have we got a plan?
Proteins
pepsin
Proteins/polypeptides
Trypsin
Oligopeptides/amino acids
Peptidases
di/-/tripeptides/amino acids
Absorption
12
Secretion into the Intestine

• Multiple glands
• Intestinal and other organs
• Large quantity (1 L/day)
• Intake of fat and protein enhance secretion
• Xenobiotics secretion via ABC transporters

13
Pattern of Intestinal Motility

• Different segment of the intestine is always in
  different phases (segmented motility pattern).
• When phase I starts at the duodenum, phase IV
  ends at the terminal ileum.
• Contraction is not as strong as the stomach, but
  it may be the continuation of stomach
  contraction.

14
Intestinal Transit
15
Effect of Food on Drug Absorption

• Gastric Emptying
• GI Secretion
• pH
• Blood Flow
• Food Binding

16
Gastric Emptying

• Enteric Coated Dosage Forms
• Drug with absorption Windows
• Riboflavin Limited absorption in upper small
  intestine.

17
GI Secretion

• Food increases bile secretion.
• Griseofulvin low dissolution rate
• Isotretinoin low dissolution rate

18
Blood Flow

• Propranolol bioavailability increases 30 when
  taken with food.
• 500 ml/min hepatic blood flow
• 670 ml/min hepatic blood flow

19
Food Binding

• Binding with Mg and Ca in the dairy products.
• Binding with protein when drug molecules have SH
  group.
• Protein R-SH gt Protein-S-R

20
Dissolution Rate

• Measures the speed of dissolution, not just the
  equilibrium solubility
• V K S Cs or V K S (Cs-C)
• Cs Cs(1Ka/H) Acid
• Cs Cs(1H/ Ka) Base

21
Topic 6 Dissolution Rate and Absorption

• Dissolution Rate
• Enhancing Dissolution Rate
• Decreasing Dissolution Rate

22
Dissolution Rate

• Determine how fast drug is dissolved in GI fluid.
• Is affected by
• Chemical form
• Crystal form
• Wetability
• Surface area

23
The Balancing Act

• Permeability
• Solubility/Dissolution Rate
• Stability Chemical/Biological (First-pass
  metabolism)
• Activity

24
GI Diseases and Malabsorption

• Alcoholism
• Intestinal Infection
• Chemotherapy
• AIDS
• Inherited Disease
• Coeliac Gluten Intolerance
• Crohns Disease Inflammatory
• Hartcup Disease Impaired AA Absorption

25
Topic 7 Intestinal Metabolism and Excretion

• Type and Variety of Enzymes
• Distribution Patterns of Enzymes
• Types and Variety of Excretion Pathways
• Distribution Patterns of Excretion Pathways
• Kinetic Consequence of Metabolism and Excretion

26
Type of Enzymes

• Phase I Enzymes
• Hydrolytic enzymes
• Oxidative enzymes
• Phase II Enzymes
• Conjugation

27
Type of Enzymes

• Drugs Enzymes Remarks
• Acetylaminophen Sulfotransferase NSAID
• Aspirin Esterases NSAID
• Alcohol Alcohol dehydrogenase Potential Abuse
• Clofibrate Esterases Hyperlipidemia (Type
  III)
• Cyclosporin P4503A Immunosuppressant
• Despiramine N-sulfotransferase Antidepressant
• Ethyinylestradiol P450 Female hormone
• Flurazepam P450 Sedative/Hypnotics
• Isoniazid Acetyltransferase Anti-TB
• Morphine Glucuronosyltransferase Analgesics/dru
  g abuse
• Sulphonamides Acetyltransferase Antibiotic
• Testesterone Glucuronosyltransferase Male
  hormone

28
Distribution Pattern of Enzymes

• Region-dependent
• Differentiation-dependent
• Diet-dependent

29
Effect of Metabolism

• Metabolism may decrease amount of drug available
  for absorption.
• Metabolism may decrease amount of drug available
  for the systemic delivery.
• Metabolism may be the basis of drug-drug,
  drug-(diet or herbal) supplement interactions.
• Metabolism may be the basis for nonlinear
  behavior in bioavailability.

30
Types of Excretion

• ABC transporters or ATP-binding cassette
  transporters.
• Specific ion transporters.

31
Effects of Excretion

• Excretion may decrease amount of drug absorbed
  into the cells.
• Excretion may be the basis of drug-drug,
  drug-(diet or herbal) supplement interactions.
• Excretion may be the basis for nonlinear behavior
  in bioavailability.

32
Differences Between Metabolism and Excretion

• Chemical vs. Physical Change
• Detoxification vs. Protection
• They can work together to prevent the entry of
  certain xenobiotics into our cells and into our
  body.

33
Combined Elimination Mechanism
34
Kinetic Effect of Metabolism and Excretion

• In the absence of drug interaction
• V Jmax C /(KmC) for efflux
• V Vmax C/(KmC) for metabolism
• In the presence of drug interaction
• V Jmax C /(KmC) for efflux
• V Vmax C/(KmC) for metabolism
• where KmKm(1Ci/Ki), Ci is the concentration of
  inhibitor, and Ki is the inhibition constant.

35
Topic 8 Biopharmaceutical Interactions

• Physical Liquid, small versus large particles
• Chemical Covalent binding of food components,
  stability of drug molecules in strong acids
• Physiological Constraint of residence or
  transit time
• Biochemical Competition for transporters and
  metabolic enzymes

36
Review

• Four Basic Concepts
• Solubility
• Permeability
• Stability Metabolic Stability
• Residence Time

37
Solubility

• Is a necessary step for drug absorption.
• Ionized vs. Unionized
• Ionized more soluble in water
• For acids, at same pH lower pKa, more soluble
• For acids, at same pKa, higher pH, more soluble
• Unionized, higher partition coefficient, which is
  a representation of lipid solubility.

38
Dissolution Rate

• Dependent on apparent solubility
• Size of particle or the surface area
• Chemical form and crystal structures
• Enhanced in the presence of surfactants and other
  wetting agents.

39
Carrier-Mediated Permeability

• Calculation V JmaxxC/(KmC)xS
• Rate of absorption is only proportional to Jmax
  and S, but not C or Km.
• In the presence of antiabsorption mechanisms such
  as p-glycoprotein and first-pass metabolism,
  effective carrier-mediated absorption decreases.
  Inhibition of these antiabsorption processes will
  enhance absorption of passively permeable drugs,
  which can lead to increased bioavailability.
  However, situation may be complicated by the fact
  that some of the measures used to inhibit or
  saturate the antiabsorption mechanisms, such as
  escalation of dose, will lead to saturation of
  the carrier, leading to a decrease in
  bioavailability.

40
Metabolic Stability

• First-pass metabolism is an antiabsorption
  mechanism that decrease the bioavailability of
  the drugs.
• First-pass metabolism is a saturable process.
• Kinetically, it behaves just like a
  p-glycoprotein mediated elimination.

41
Metabolic Stability

• Inhibition of metabolism is a leading and common
  cause of drug-drug, drug-nutrient, and drug-herbs
  interactions.
• Some molecules (e.g., protein and polypeptides)
  are not delivered through the oral route because
  of their poor stability in the GI tract prior to
  and after oral absorption.

42
Residence Time

• Controls the onset of drug based on dosage form
  design and diet.
• Controls the minimum frequency of dosage
  administration.

43
Key to Exam

• Selection of appropriate equations
• Use of logic and proportion
• efficiency
• accuracy
• Unit conversion
• Result interpretation
• Poise and time management

44
End of Oral Drug Delivery