Gastrointestinal System PR2152

Gastrointestinal System Lecture Notes

• The lecture covers PK concepts for distribution.
• The course is PR2152.
• The semester is AY2024/25 Sem 1.
• The instructor is Chng Hui Ting, PhD.
• Email: [email protected]

Overview of Distribution Lectures

• Part 1: Factors affecting drug distribution
  • What factors influence drug distribution?
  • Not all drugs distribute instantaneously. How do we describe the disposition of drugs that don't distribute instantly?
  • What is the clinical relevance of understanding multi-compartmental models for drug disposition?
• Part 2: PK parameters from two-compartment models
  • What PK parameters can be derived from a drug's profile following IV bolus administration in a two-compartment model?
  • What factors affect the rate of drug distribution?

Learning Outcomes (Part 1)

• Students will be able to explain the factors affecting drug distribution using protein binding equations and tissue distribution models.
• Students will be able to relate the fundamental concepts of drug distribution to their clinical relevance.
• Students will be able to describe PK processes and different apparent volume of distributions associated with drugs following a two-compartment model.

Body Water and Compartments

• Total body water (70 kg person): 42L
• Intracellular water (VR) = 27L
• Extracellular water
  • Intravascular (plasma) = 3L
  • Extravascular (interstitial) = 12L

Primary PK Parameter - Apparent Volume of Distribution

• Big idea: The apparent volume of distribution (V) represents the fluid volume in which a drug distributes to account for its concentration in plasma.
• V relates the amount of drug in the body to the plasma concentration.
• V may be defined with respect to blood, plasma, or water, depending on the specific concentration used in the calculation.

Clinical Application of V

• Protein drugs often have V values similar to plasma volume due to their large size, hindering their ability to cross cell membranes.
• Basic compounds tend to have larger Vs than acidic compounds.
• Digoxin is neutral, while Amphotericin B is both an acid and a base.

Plasma and Tissue Protein Binding

• Concept: Unbound fraction (fu)
  • Blood/Plasma: fu = Cu / Cp
  • Tissues: fur = CuT / Cr
• There are several equilibria to consider, including:
  • The bound-unbound equilibrium in plasma/blood
  • The bound-unbound equilibrium in tissues
  • The equilibrium between blood and tissue compartments.
• Examples of plasma proteins binding to drugs?

Factors Affecting the Extent of Drug Distribution

• Factors affecting plasma protein binding (e.g., fu)
• Factors affecting tissue protein binding
• Factors affecting tissue volume

Acidic vs. Basic Drugs

• Acidic: Tend to have a smaller volume of distribution (<1 L/kg) due to high affinity for plasma albumin and low affinity for tissues. Drugs like Tolbutamide have V = 0.15 L/kg and f₁ = 5–10%.
• Basic: Typically have a larger volume of distribution (>1 L/kg). Propranolol, for example, has V = 4L/kg and f₁ = 5–10%.

Tissue-to-Plasma Equilibrium Ratio

• Kp is the tissue-to-plasma equilibrium distribution ratio, which varies from one tissue to another.
• Equilibrium is reached when the net flux of free drug movement is zero (CuT = Cp).

Model of Tissue Distribution

• Amount in body = Amount in plasma + Amount outside plasma
• VC = VpCp + VTCT (1)
• V = Vp + VT* (f u T / f u )

Model of Tissue Distribution (Continued)

• At distribution equilibrium: Amount in body = Amount in plasma + Amount outside plasma VC = Vp * Cp + VT * CT (1) V = Vp + VT * (CT/Cp) (2)

Model of Tissue Distribution (Continued)

• Since, fu = Cu/Cp and fur = CuT/CT (3)
• Substitute (3) into (2): V = Vp + VT*fuT/fu (4)

Model of Tissue Distribution (Continued)

• This equation relates the apparent volume of distribution (V) to the volume of plasma (Vp) and the total volume of other tissues (VT). This is important in assessing how a drug distributes throughout a body.

Gibaldi and McNamara Model

• Looking at the equation V=Vp + VT *(fuT / fu ), the term fuT/fu is a measure of the relative binding of a drug between plasma and tissues.
• Aids in interpreting data on V, enabling estimation of fut, which is the average value across all tissues into which the drug distributes

Plasma Protein Binding

• Free drug fraction (fu): fu =(1+KafupPT)⁻¹
  • Ka=association constant
  • Cup =concentration of unbound drug
  • PT=concentration of total binding protein.
• Factors affecting free drug fraction (fu) include alterations to total protein and diseases.

Factors Affecting Free Drug Fraction (fu)

• Diseases
• Genetic variants of albumin, or a₁-AGP .
• Drug-drug interactions.

Calculating Changes in fu

• fu = 1 / (1 + Ka * fup * Pr)
• For drugs with low fu, we can approximate fu =1 / (Ka * fup * Pr)
• If the total protein (Pr) changes, a new fu can be calculated using the same equation.

Impact of Change in fu on V

• For drugs with large V, changes in fu lead to a proportional change in V.
• For drugs with small V, changes in fu have minimal impact on V.

Impact of Change in fu on CL

• For drugs with high extraction ratio ( > 0.7), changes in fu have minimal impact on CL.
• For drugs with low extraction ratio ( <0.3 ), changes in fu result in changes in CL.

Factors Affecting fu, fut, and V₁

• Plasma Protein Binding (fu): Disease, genetic variations, drug interactions.
• Tissue Protein Binding (fut): Genetic variations, drug interactions.
• Tissue Water (Vt): Altered physiology (e.g., pediatrics, geriatrics, pregnancy), pathology (e.g., liver or kidney disease).

Impact of Change in fut on V

• V = Vp + VT *(fut / fu)
• fut represents the average value across all tissues into which the drug distributes.

Clinical Relevance of Multi-compartmental models

• Minimizing the need to draw too many blood samples during therapeutic drug monitoring (TDM).
• Correct timing of sampling is critical especially for drugs that exhibit a two-compartment model, for example, aminoglycosides, digoxin, and lithium.
• Avoid erroneous determination of elimination half-life which would result in improper dose adjustments

Two-compartment Model

• Assumptions:
  • Drug distributes instantaneously throughout the central compartment.
  • Drug in tissues of the peripheral compartment reaches equilibrium with the central compartment after some time.

Two-compartment Model - PK Processes

• I: End of Injection: Central compartment is quickly filled, some drug may transfer to the peripheral compartment.
• II: Distribution Predominates: Central compound elimination & initial rate of drug transfer between central and peripheral compartment.
• III: Distribution equilibrium: Rapid transfer between central and peripheral compartments, resulting in equilibration.
• IV: Elimination predominates: The central compartment elimination becomes dominant.

Different Apparent Volumes of Distribution

• Vc: Volume of central compartment
• Vs: Volume at steady-state.

Two-, Three-, Four- etc Compartment Model

• Compartmental models are useful for describing how drug concentration changes over time in the body.
• The number of compartments (e.g., one, two, three) needed depends on how many exponential terms are required to model the data.

Trend of Decline of Drug Concentration

• A one-compartment model predicts a single exponential decline in plasma drug concentration over time.
• A two-compartment model predicts a bi-exponential decline in plasma drug concentration over time.

This quiz covers the key pharmacokinetic (PK) concepts related to drug distribution as part of the Gastrointestinal System course (PR2152). Students will explore various factors influencing distribution, the relevance of multi-compartmental models, and the parameters derived from two-compartment models. Understanding these concepts is essential for effective drug administration and therapy.