Lecture 6 - Absorption and bioavailability

Lecture on Absorption Models and Bioavailability

Introduction to Absorption Models

• Absorption models serve as mathematical or conceptual representations of how drugs move from the administration site into systemic circulation.

• They predict how quickly and how much drug is absorbed, essential for designing effective dosing regimens and achieving therapeutic effects.

Learning Outcomes

1. Differentiate between first order and zero order absorption models.

2. Define and distinguish absolute and relative bioavailability.

3. Identify key factors affecting bioavailability.

4. Explain the concept and regulatory importance of bioequivalence.

Absorption Models

First Order Absorption Model

• Definition: The drug absorption rate is proportional to the remaining drug amount at the absorption site.

  • Absorption is faster when there is more drug available; it slows down exponentially as the amount decreases.

  • Characterized as concentration-dependent and non-saturable.

• Mathematical Representation:

  • Rate of absorption: $\frac{dA}{dt} = -K_a \cdot A$

  • Where:

  • $A$ = amount of drug at the absorption site

  • $K_a$ = first order absorption rate constant.

• Graph Interpretation:

  • Concentration-time graph shows increasing absorption with high concentration, followed by an exponential decrease in concentration over time.

• Half-life Calculation:

  • Absorption half-life formula: $t<em>{1/2} = \frac{0.693}{K</em>a}$

Zero Order Absorption Model

• Definition: The rate at which the drug enters the bloodstream is constant, independent of the remaining drug concentration.

  • Drugs are absorbed at a constant rate, typically seen in controlled release formulations or drugs with limited solubility.

• Mathematical Representation:

  • Rate of absorption: $Rate = -K_0$

  • Where:

  • $K_0$ = zero order absorption constant.

• Graph Interpretation:

  • Concentration-time graph shows a linear decrease in drug amount remaining over time, indicating a constant amount absorbed per time unit.

Lag Time

• Definition: The delay between drug administration and the appearance of the drug in systemic circulation, particularly noticeable in oral administration.

  • Represents the time interval when plasma drug levels are essentially zero before absorption starts.

• Causes of Lag Time:

  1. Delayed gastric emptying (slower stomach emptying results in prolonged time to reach small intestine).

  2. Enteric-coated formulations (designed to dissolve later).

  3. Presence of food (can either enhance or delay absorption).

Bioavailability

• Definition: The rate and extent of absorption of unchanged drug from its dosage form into systemic circulation, denoted as 'F'.

  • Also referred to as 'systemic availability'.

• Calculating Bioavailability:

  • $F = \frac{\text{bioavailable dose}}{\text{administered dose}}$

  • For IV administration, bioavailability is 100%, while for oral administration, it's usually less than 1 due to losses (incomplete absorption, first-pass metabolism, degradation by stomach acid).

• Importance of Bioavailability:

  • Dose Selection: Determines how much of a drug to administer to achieve desired effects.

  • Therapeutic Effect and Safety: Poor bioavailability can reduce drug effectiveness; excessive absorption can increase side effects.

  • Critical in Drug Development: Important for designing drug formulations to maximize bioavailability.

Types of Bioavailability

1. Absolute Bioavailability (F): Measures the fraction of the drug that reaches systemic circulation after oral administration compared to IV administration.

   • $F = \frac{AUC<em>{oral}}{AUC</em>{IV}} \cdot \frac{Dose<em>{IV}}{Dose</em>{oral}}$

2. Relative Bioavailability (F_relative): Compares bioavailability between two formulations of the same drug.

   • Formula: $F<em>{relative} = \frac{AUC</em>{test}}{AUC<em>{reference}} \cdot \frac{Dose</em>{reference}}{Dose_{test}}$

   • Example: Comparing bioavailability from a tablet versus a capsule form.

Factors Affecting Bioavailability

Drug-Related Factors

• Solubility: Poorly soluble drugs lead to reduced absorption and bioavailability.

• Stability: Drugs must be chemically stable in the GIT; for example, insulin degrades in stomach acid.

• Lipid Solubility: More lipid-soluble drugs penetrate cell membranes more easily (e.g., diazepam).

• First Pass Metabolism: Some drugs are metabolized by the liver before reaching systemic circulation, reducing bioavailability (e.g., propranolol).

• Chemical Form: The drug's form affects its dissolution; salts often improve bioavailability (e.g., sodium phenytoin vs. free acid).

Physiological Factors

• Gastric Emptying Time: Faster gastric emptying allows quicker absorption.

• Intestinal Motility: Rapid intestinal movement can decrease absorption time.

• Gastrointestinal pH: Affects drug ionization and solubility; example with ketoconazole.

• Blood Flow: Adequate blood flow enhances absorption.

• Food Interaction: Food can alter absorption; e.g., tetracyclines shouldn't be taken with milk.

Pharmaceutical Factors

• Dosage Form: Solutions absorb faster than tablets; e.g., paracetamol in solution formulation works better than standard tablets.

• Particle Size: Smaller particles improve dissolution and absorption.

• Disintegration Time: Longer-lasting tablets lead to slower absorption.

• Excipients: Inactive ingredients can influence absorption positively or negatively.

Route of Administration

• Different routes influence the extent and speed of absorption, e.g., IV provides 100% bioavailability, while oral generally provides less due to absorption losses.

• First Pass Metabolism: Affects drugs absorbed from the gut before reaching circulation.

• Systemic Availability: Combined effects of absorption and first-pass metabolism define how much active drug reaches the bloodstream.

Bioequivalence

• Definition: Term denoting that two dosage forms of a drug reach systemic circulation at the same relative rate and extent.

• Importance: Before a generic drug is marketed, it must demonstrate bioequivalence to the brand name product to ensure consistent therapeutic effect when switching medications.

Related Terms

1. Chemical Equivalence: Identical active ingredients in the same dosage amount.

   • Example: 500 mg paracetamol in both tablet and capsule forms.

2. Pharmaceutical Equivalence: Same active ingredient and strength, same dosage form, meeting quality standards, possibly with different excipients.

   • Example: Branded vs. generic formulations meeting the same standards.

3. Therapeutic Equivalence: Same active ingredient produces equivalent clinical effects and safety profiles.

   • Example: Panadol vs. generic paracetamol relieving headaches equally.

Significance of Bioequivalence Studies

• Confirm generic equivalency to brands ensures consistent absorption rate and extent.

• Avoid the need for large-scale clinical trials for generics, promoting affordability and accessibility to essential medicines.

• Supports competition and innovation in the pharmaceutical market, reducing healthcare costs.

Conclusion

• The study of absorption models and bioavailability is crucial for understanding drug behavior within the body and ensuring effective and safe therapeutic outcomes.