Drug Absorption and Bioavailability

Drug Absorption

• Refers to the extent a drug is absorbed from the gut into the portal circulation
• This is shown as a fraction of the dose absorbed from the gut, notated as (Fg)
• The extent a drug is removed by the liver to the systemic is called first pass clearance (Fh)
• Bioavailability is the fraction of a dose that reaches systemic circulation as an intact drug (F)
• Bioavailability (F) is calculated by the following equation F = Fg x Fh

Drug Concentration in Plasma

• Viewing plasma concentration has the most direct approach to measauring drug absorbtion
• It is assumed that the drug in plasma is in dynamic equilibrium with tissues
• Changes in drug concentration in plasma reflect changes in tissue drug concentration
• As a drug is absorbed into systemic circulation, drug concentration in plasma will rise to a maximum
• Simultaneously, the drug is distributed to tissues and eliminated

Routes of Drug Administration

• Oral route
• Buccal route
• Rectal route
• Intravenous route
• Inhalation route
• Topical route
• Administered via Skin or Vaginally
• Nasal or Eyes
• GIT administration will be either local or systemic

Physiological Factors Affecting Oral Absorption

• Membrane characteristics
• Transport mechanisms
• Route of administration
• Gastric emptying rates
• Ionization factors

Membrane Physiology

• In 1990, Overton determined that lipid molecules cross frog muscle membranes
• He also found that larger, lipid-insoluble molecules could not cross, and smaller polar compounds slowly crossed
• Membranes act as lipid barriers
• Membranes have small holes with different pore sizes and characteristics

Examples of Membranes and Their Properties

• Blood/brain membranes: Allow only lipophilic drugs
• Blood/kidney (Bowman's) membranes: Lipid membranes with larger pores allow both lipophilic and hydrophilic drugs
• Blood/kidney (tubuli) membranes: Lipid membranes allow only lipophilic drugs
• Lung membranes: Lipid membranes with pores allow both lipophilic and hydrophilic drugs
• Stomach membranes: Lipid membranes with few pores allow lipophilic, non-ionized acidic drugs
• Small intestine membranes: Lipid membranes with few pores allow lipophilic acidic and basic drugs but less hydrophilic drugs

Transport Across Membranes

• Carrier mediated transport

Carrier Mediated Transport

• Active transport
• Facilitated transport
• Passive transport
• Pinocytosis
• Ion pair transport

Active Transport

• Requires a carrier molecule and a form of energy (e.g., glucose)
• The process can be saturated; the a lot of carriers and a lot of substrate.
• Transport that proceeds against a concentration gradient
• This can have competitive inhibition

Facilitated Transport

• Requires a drug carrier but does not require energy
• Vitamin B12 transport is an example
• This is saturable if there are not enough carriers present
• There is no transport against a concentration gradient, just downhill, but faster

Passive Transport

• Diffusion occurs when drug concentration is higher on one side of the membrane
• Drug diffuses across the membrane to equalize concentration on both sides
• The rate of transport is described by Fick's Law of Diffusion: = D x A x (Ch – Cl) / X -D: Diffusion Coefficient x Surface Area x (Concentration difference) / Membrane thickness

Fick's Law of Diffusion Details

• D is the diffusion coefficient, which relates to the size and lipid solubility of the drug, the viscosity of the diffusion medium, and the membrane
• A is surface area; as surface area increases, the rate of diffusion also increases
• Absorption is generally faster from the intestine compared to the stomach
• X is membrane thickness; the smaller the membrane thickness, the quicker the diffusion (lung tissue)
• (Ch – Cl) measures the concentration difference.
• Drug concentration in blood or plasma is usually less than the concentration in the gut.
• This concentration gradient allows for rapid, complete absorption of drug substances

GI Physiology

• Buccal pH is approximately 7 and offers through thin membranes
• It's blood supply encourages good and fast absorbtion with low doses and short transit time
• Does By-pass the liver
• Oesophagus pH is 5-6 and is thick with no absorbtion and short transit time
• Stomach pH is 1-3 and is normal with good blood supply but longer transit time and does not bypass the liver
• Duodenum pH is 6-6.5 with normal membranes and good blood supply, very short travel time and doesn't bypass the liver
• Small Intestine pH is 7-8 with normal membranes and good blood supply, about 3 hours
• Large Intestine is pH 5.5-7 with good blood supply and long transit time

Gastric Emptying and Motility

• Drugs are generally better absorbed in the small intestine than the stomach
• Therefore, faster stomach emptying increases drug absorption
• Slower stomach emptying can cause increased degradation of drugs due to lower pH
• A correlation exists between stomach emptying time and peak plasma concentration for paracetamol
• A faster stomach emptying rate means a higher concentration of paracetamol

Effect of Food on Gastric Emptying

• Fatty food can slow gastric emptying and retard drug absorption
• The absorption extent is generally not greatly reduced
• Griseofulvin absorption is improved by fatty food because it dissolves the poorly soluble griseofulvin
• Propranolol plasma concentrations are larger after food, possibly due to interaction between the drug and food components

Factors Affecting Gastric Emptying and Motility

• Volume of ingested material (initially increases, then decreases emptying rate; bulky materials empty more slowly)
• Type of meal (fatty and carbohydrate both decrease rate)
• Temperature: increase in temperature, increases the emptying rate
• Body position (lying on the left side decreases the emptying rate; standing versus laying is delayed)

Drugs That Delay Gastric Emptying

• Alcohol
• Aluminum hydroxide antacids
• Anticholinergics
• Beta agonists
• Calcium channel blockers
• Cyclosporine (Sandimmune)
• Diphenhydramine (Benadryl)
• Glucagon-like peptide-1 analogs e.g., exenatide [Byetta]
• Histamine H₂-receptor antagonists
• Levodopa
• Lithium
• Ondansetron (Zofran)
• Opioids
• Phenothiazines
• Proton pump inhibitors
• Tricyclic antidepressants

Physical-Chemical Factors Affecting Absorption

• pH partition theory
• For weak bases or acids, the pKa of the drug, the pH of the GIT fluid, and the pH of the blood stream control solubility
• These factors affect the rate of absorption through the membranes lining the GIT
• pH and drug pKa influence drug transfer or absorption
• Drugs are only able to get through the lipid membrane when they are non ionized and have higher lipid solubility

Role of pH in Ionization of a Weak Base/Acid

• As pH increases, a weak base will become more unionized, lipid soluble, and better absorbed
• As pH decreases, a weak base will become more ionized, lipid insoluble, and will not be absorbed
• As pH increases, a weak acid will become more ionized, lipid insoluble, and will not be absorbed
• As pH decreases, a weak acid will become more unionized, lipid soluble, and better absorbed

Partition Coefficient (pKa)

• pKa is the pH at which 50% of the drug is ionized and 50% is unionized
• pKa quantifies the strength of an acid in a solution
• pKa stands for the negative logarithm of the acid dissociation constant (Ka) of a solution
• The lower the pKa value, the stronger the acid; a lower value indicates the acid more fully dissociates in water

Applications of pKa

• Essential for understanding acid behavior and predicting pH in solutions
• It selects appropriate buffers considering the relationship between pKa and pH
• When choosing a buffer, the best option is one with a pKa value close to the target pH of the solution

Ionization

• Weak Acid: Log I/U = pH – pKa
• Weak Base: Log I/U = pKa – pH
• % Unionized = U / (I + U) X 100 (U will always equal to 1)

Henderson-Hasselbalch Equation

• Expresses the ratio of lipid-soluble form to water-soluble form for a weak acid or base
• Relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pKa and the pH of the medium
• pH = pKa + log (unprotonated form / protonated form)

Henderson-Hasselbalch and Absorption

• For a weak acid, the pH minus pKa is low then it is more non-ionized and better absorbed
• For a weak base, the pH minus pKa is high then it is more non-ionized and better absorbed

Drug Dissolution

• Solid dosage form → Coarse granules → Fine granules/primary particle → Drug in Solution → Drug in micro or nano form.

The Diffusion Layer

• Each particle of the drug formulation is surrounded by a stagnant layer of solution
• Drug dissolution is diffusion-controlled

Relationship Describing Dissolution

• dm/dt = D A (Cs – C) / h
• dm/dt is rate of dissolution
• D = diffusion coefficient of drug
• A = surface area of the dissolving drug
• Cs = solubility of drug in diffusion layer
• C = solubility of drug in bulk GI fluid
• h = thickness of the diffusion layer