Biopharmaceutics

GIT- Barriers to Drug Absorption (and Mechanisms of Drug absorption)

Lec:3

Ali Y Ali BSc Pharmacy

MSc Industrial Pharmaceutical Sciences

Dept. of Pharmaceutics College of Pharmacy

University of Sulaimani

Overview Barriers to drug absorption• Environment within the GIT

• GIT pH• Luminal Enzymes • Food inside the GIT • Disease state and physiological conditions

• Unstirred water layer • GIT membrane

• Structure of Membrane • Mechanisms of drug absorption

• Transcellular • Paracellular • Efflux of drugs from GIT

• Presystemic Metabolism • Gut wall • Hepatic

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Barriers to Drug absorption

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http://www.hilmersstudios.com/medical

Environment within GIT 1. GIT pH

2. Luminal Enzymes

3. Food inside the GIT

4. Disease state and physiological conditions

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Gastrointestinal (GIT) pH

• It varies along the GIT

• Stomach: • Fasted state: 1-3.5

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GIT pH• Fed state: the gastric juice is buffered

to a less acidic depending on the food composition pH 3-7.

• The cycles returns to the fasted pH after 2-3 hours, depending on the size of the meal

• Only dosage forms taken during or straight after meal will encounter this.

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pH 3-7

• Intestinal pH: • Higher than gastric juice

owing to pancreatic secretion of bicarbonate • Gradual increase from

duodenum to ileum

• Colon:• pH drops again

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Effects of pH

Effects

Chemical Stability

Rate and Extent of

Dissolution

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Chemical Stability

• pH dependent hydrolysis • Penicillin G( Benzyl penicillin)

• Penicillin G degradation in the stomach depends on • GER

• Gastric pH

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Erythromycin

• Erythromycin rapidly degraded

• Prodrug

• Gastro-resistant tablet

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Proton Pump Inhibitors • Omeprazole & Esomeprazole• used in the treatment of peptic

ulcers.

• Enteric coated tablet

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Luminal Enzymes

• Gastric juice:• Pepsin;

• protein and peptide drugs undergo decomposition

• Intestinal:• Lipases: release of drug that has fat/oil containing dosage forms • Proteases• Amylases • Drug of nucleotide and fatty acid bases or containing esters – hydrolysis

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Colon:• Bacteria producing enzymes e.g. azo-reductase

• This enzyme has been exploited for the design of prodrugs • Sulfasalazine: 5ASA---Azo---- Salazopyridine

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Food inside the GIT 1. Complexation with components in the food 2. Alteration of pH 3. Alteration of GER 4. Stimulation of GIT secretions 5. Competition between food components and

drugs for specialised absorption mechanisms 6. Increased viscosity of the GIT contents 7. Food induced changes in presystemic

metabolism 8. Food induced changes in the blood flow

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`1. Complexation with components in the food • reversible water soluble complexes are not problematic • Irreversible complex, reduction of the amount of the drug

available for absorption• e.g. Tetracyclines forms non absorbable complex with

Calcium and Iron ions

• It is not taken with milk and Iron preparations

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2. Alteration of pH: increase gastric pH by acting as a buffer• Dissolution of Weakly basic drugs reduced, however of acidic

drugs increased.

3. Alteration of GER: • Fat containing foods reduce GER

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4.Stimulation of GIT secretions: Gastric secretions (Pepsin) and bile. • Bile: surface active agent, forms insoluble complex

• Neomycin

5. Competition between food components and drugs for specialisedabsorption mechanisms

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6. Increased viscosity of the GIT contents:

• Dissolution reduced • Diffusion from lumen to the membrane reduced

7. Food-induced changes in presystemic metabolism :• Grapefruit juice: inhibit metabolic enzymes.• Increase bioavailability of drugs undergo metabolism • verapamil, ciclosporin

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8. Food induced changes in the blood flow• Increase blood flow • Rate of presentation to the liver • Drugs metabolised by liver; bioavailability increased • Saturation of the enzymes • Propranolol & Hydralazine

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Effects of Food on absorption

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Disease state and physiological disorders

• Local disease:• alteration in pH –stability and dissolution

• Gasterectomy: surgical removal of part or whole stomach, faster presentation of drugs to intestine.

1. Drugs absorbed from intestine: higher bioavailability 2. Drugs needs dissolution in the stomach: reduced bioavailability

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Disease state and physiological disorders

• AIDS patients

• Hypochlorhydria

• Adversely affect the dissolution and hence bioavailability of weakly basic drugs • anti-fungal ketoconazole

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Coeliac disease

• Inflammatory disease affecting the proximal small intestine

• Gluten, protein found in cereals and grains

• Patients with coeliac disease 1. Faster GER 2. Increased permeability of the small intestine

• Cephalexin absorption appears to be increased in celiac disease

Unstirred water layer

• Mucus, water, glycocalyx • 30-100 µm thickness

1. Diffusion barrier 2. Complexation with mucus

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GIT membrane

• Structure of Membrane

• Mechanisms of drug absorption

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Structure of membrane

• The main cellular barrier for absorption. • Complex: protein, lipid, lipoproteins and polysaccharide.

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Structure of membrane • Semi-permeable membrane• Permeable: amino acids, fatty acids and sugars

• Impermeable: plasma proteins

• Semi-permeable sieve: allows lipid-soluble molecules across it and the hydrophilic molecules and water will be transported through the pores

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• Transporter proteins and carrier molecules that transport materials back and forth.

Mechanisms of transport across the membrane

1. Transcellular: across the cells 1. Passive diffusion 2. Carrier mediated

transport 3. Endocytosis

2. Paracellular: between cells

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Mechanisms of transport across the membrane• Passive

• Active

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Passive diffusion • Most drugs absorbed

• Movement of moleculesacross a semi-permeable membrane from a region of high concentration to a region of lower concentration.

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Rate of Diffusion

1. Physicochemical properties• Lipid solubility

2. Nature of the membrane

3. Concentration gradient • Dissolution • Sink condition

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Passive diffusion • Fick’s First Law of diffusion

• dC/dt: rate of appearance of drug in the blood at the absorption site • P : permeability coefficient • Cg: concentration of the drug in solution in the GIT fluid at the absorption site • Cb: concentration of the drug in the blood at the absorption site

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𝑑𝐶𝑑𝑡

= 𝑃(𝐶' − 𝐶))

• D: diffusion coefficient of the drug in the GIT• A: surface area of membrane • K: partition coefficient • h : thickness of the wall

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𝑃 =𝐷 𝐴 𝐾ℎ

Rate of diffusion

1. Diffusion coefficient (D)

2. Surface area of absorption (A): • Small intestine is the major site of absorption

3. Partition coefficient (K)

4. Thickness of the wall (h)

5. Concentration gradient (Cg-Cb)

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𝑑𝐶𝑑𝑡

=𝐷 𝐴 𝐾ℎ

(𝐶' − 𝐶))

• Partition coefficient of the drug from GIT fluid to the membrane

• Partition coefficient of the drug from the membrane to the blood

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Partitioning

Passive diffusion stops after balance ?

• The concentration gradient is kept at the site of the absorption by the blood which acts as a ‘sink’ • Distribution • Metabolism • Excretion • Protein binding

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Sink Condition

• All these makes Cg >>>> C b

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𝑑𝐶𝑑𝑡

= 𝑃(𝐶' − 𝐶))𝑑𝐶𝑑𝑡

= 𝑃(𝐶' − 0 )

Sink Condition

• D, A,K and h can be considered as constant P

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𝑑𝐶𝑑𝑡

=𝐷 𝐴 𝐾ℎ

(𝐶')

𝑑𝐶𝑑𝑡

= 𝑃 𝐶'

Passive diffusion

• The process follows first order kinetics

• Drugs are weak electrolytes so undergo dissociation based on theirpKa and pH of the environment in to ionised and unionised forms.

• Unionised is more lipophilic so more permeable form.

• Hence the rate of absorption is dependent on the concentration of the unionised form.

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Ionization

• Acids

• Bases

Example

• Salicylic acid pKa is 3

a. Gastric Juice : pH = 1.2

a. Plasma : pH = 7.4

Examples

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Carrier-Mediated transport

1. Active transport

2. Facilitated diffusion

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Active Transport

• Mechanism of transport of drugs which involves carrier molecules and use of energy by cells in form of ATP.

• It can be from a lower concentration to a higher concentration.

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Active Transport

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The process of Active Transport

Carrier or transporters involved 1. Structure specificity:

• Competition between structurally similar molecules (drugs)

2. Energy is used: metabolic inhibitors will reduce the process

3. Saturable

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Site of the Carriers

• Carriers are concentrated in a certain place in the GIT: • Bile salt transporters are condensed and located in the ileum

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Passive Vs Activated Transport

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Transporters• Peptide • Nucleoside • Sugar • Amino acid• Bile acid • Organic anions • Vitamins: Thiamin B1, nicotinic acid, Riboflavin B2,

Pyridoxine B6, cobalamin B12

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Transporters

• Peptide like drugs: Penicillins, cephalosporins, ACE inhibitors

• Nucleoside analogues: antivirals

• Amino acid : L-Dopa and methyldopa• L-Dopa has faster permeability due to the lower affinity of the methyl dopa to

the transporters

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Facilitated Diffusion

• Carrier mediated • Saturable process • It is not against concentration gradient • It does not use energy

• Minor role in drug absorption

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Endocytosis (Vesicular Transport )

• Is the process in which the cell membrane invaginates and surrounds a certain material, this invagination forms vesicles.

• Then the material will be transferred to other vesicles or to lysosome for digestion

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Endocytosis

• Some materials escape digestion and exocytosed.

• Energy dependent

• Macromolecules

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Types

1.Pinocytosis (fluid-phase endocytosis)

• Engulfment of the extracellular fluid by membrane vesicles, the internalization is regardless of its importance to cells.

• Vitamins E, D, A, K.

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2. Receptor mediated endocytosis

• Receptors on the cell surface

• The vesicles end up in the lysosomes where is a place of digestion

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3.Phagocytosis: particles > 500 nanometre• Vaccines

• Polio vaccine

4. Transcytosis: material is internalized and transferred across the cell to the other side of the cell.

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500 nm

Absorption through the Lymphatic System

• Lipophilic drugs may be absorbed through the lacteal or lymphatic vessels

• The lymphatics are important in the absorption of dietary lipids • Partially responsible for the absorption of lipophilic

drugs

• The lymphatic system bypasses the liver and avoids the first-pass effect • Lymphatic vessels drain into the vena cava rather than

the hepatic-portal vein.

Absorption through the Lymphatic System

• Many poorly water-soluble drugs are soluble in oil and lipids• May dissolve in chylomicrons and be absorbed systemically via the lymphatic

system.

• Examples • Bleomycin was prepared in chylomicrons to improve oral absorption through the

lymphatic system (Yoshikawa et al, 1983, 1989). • Testosterones

Paracellular Pathway • Transport through aqueous pores between

the cells.

• They occupy only 0.01 % of the total surface area of epithelium.

• Tightness of junctions vary• Small intestine is leakier.

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Paracellular Pathway

• Small hydrophilic and charged drug can be absorbed when they cannot be absorbed transcellularly.

• 200 Dalton

• Passive diffusion or convective

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• Ions, sugars, amino acids and peptides above capacity of carriers.

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Efflux of drugs from the intestine • Counter transport efflux proteins that

expels drug back into the GIT lumen

• P-glycoprotein : expressed at high levels in jejunum.

• Bioavailability reduction

• Similar mechanism of active transport

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Efflux of drugs from the intestine

• Energy required

• Against concentration gradient

• Saturable process and can be competitively inhibited

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Presystemic Metabolism • First-pass metabolism• Cytochrome CYP P450

1. Gut wall

2. Hepatic

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Presystemic Metabolism • Primary site of metabolism

• Considerable reduction in Bioavailability• Oral ineffective • Vey large dose compared to IV,

Propranolol

• Propranolol is well absorbed• only 30% available

• Lidocaine• Imipramine (TCA)

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Barriers to Drug absorption

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Further Readings • Aulton, M. E. and K. M. Taylor (2013). Aulton's pharmaceutics: the design

and manufacture of medicines, Elsevier Health Sciences.• Shargel, L., S. Wu-Pong and A. B. Yu (2007). Applied biopharmaceutics &

pharmacokinetics, McGraw-Hill.• Fleisher, D., B. Sweet, A. Parekh and J. Boullata (2010). Drug Absorption with

Food. Handbook of Drug-Nutrient Interactions. J. I. Boullata and V. T. Armenti, Humana Press: 209-241.• Lake-Bakaar G, Tom W, Lake-Bakaar D, Gupta N, Beidas S, Elsakr M, et al.

Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988;109(6):471-3.

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Videos

• https://www.youtube.com/watch?v=IOf-z0D1mHk• https://www.youtube.com/watch?v=xiuWdJYyIKs• https://www.youtube.com/watch?v=uej8IDhjvZg

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