2011B02 What is meant by the term “two compartment model” in pharmacokinetics?
Use propofol as an example in explanation.

 

List:

·      Intro

·      Two compartments: features

·      Two compartments: sources of error

·      Alternative models

 

Intro:

Aim of pharmacokinetic model: to predict drug concentration during induction, maintenance and offset of anaesthesia

 

Two compartment model: features

Diagramme

Graph and equation

·  Bi-exponential decay curve: C = Ae-at + Be-bt

Description

·  Propofol injected into V1

·  Effect correlates with [propofol] in V1

·  Fast distribution phase (distribution+++ metabolism ++)

·  Slower terminal elimination phase (metabolism++ offset by redistribution+)

Derivation

·  Experiment in healthy volunteers

·  Propofol infusion at various rate, various duration (1min to 8h)

·  Serial blood sampling

·  Plot Cp vs time

·  Non-linear regression analysis -> equations, rate constants, compartment volumes

Suitability of propofol

·  Reasonably modelled by two compartments (VDC 0.3-0.6L/kg, VDSS 4L/kg)

·  Rapid distribution (t1/2α fast 2 mins, t1/2α slow 50 mins)

·  Slow terminal elimination (t1/2β 5-12 hours)

 

Two compartment model: sources of error:

Inaccurate modelling

·   Body has billions of discrete cell compartments, not 1 or 2 or 3

·   Variation in compartment volumes (e.g. shock), clearance rate (e.g. organ failure)

·   Inaccurate for induction kinetics (cardiac output and central blood volume more important)

·   Small sample size of experiments

Inaccurate assumptions

·   No delay between reaching threshold Cp and onset of effect (e.g. lag described by ke0)

·   [Drug] in V1 correlates immediately with effect (e.g. effect site may be in periphery e.g. rocuronium)

·   Elimination always from V1 (e.g. remifentanil metabolized in periphery)

·   Elimination not always first order (e.g. thiopentone zero order in physiological range)

Consequences of error

·   Overdose -> CVS toxicity

·   Underdose -> awareness

 

Alternative models:

Single compartment

·   Not a good representation

·   Whole-body equilibration not immediate

·   Predicted loading dose based on VDSS is fatal

Three compartment

·   Better model for most drugs

·   E.g. propofol: t1/2α fast, t1/2α slow and t1/2β

Four or more compartments

·   No significant advantage over three

 

 

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