Pharmacokinetics: 2 compartment modelling

How to calculate Vdss

Approximate Vdss from Vdarea CL=Ke*VD and CL=D/AUC Equating and solving, we get Vdarea=Dose*F/(AUC*Ke)

Causes of non-linear pharmacokinetics

Changes in clearance - due to renal insufficiency Changes in volume of distribution - due to rapid redistribution of drug to peripheral compartments (loss of blood) Changes in half life due to induction or inhibition of CYP450 enzyme system. Changes in saturable protein binding or metabolism

Alpha phase

Distribution of drug to tissues. A curved line as equilibrium has not been reached yet.

Kinetic order of elimination

During the beta elimination phase there is: First order kinetics - elimination rate of drug is independent of drug concentration (eliminations mechanisms are saturated) Second order kinetics - elimination rate of drug is related to drug concentration (not all elimination mechanisms are saturated, hence drug is cleared at an increasing rate). This produces a logarithmic curve.

Suitability of two compartment model

For drugs that distribute to peripheral tissues.

Suitability of one compartment model

For drugs that remain within the central compartment.

Effect of genetics on pharmacokinetic parameters

Genetic polymorphism on liver enzyme systems can effect rates of clearance.

Beta phase

Metabolism/excretion of drugs. This is a straight line and we make the calculations from this phase.

Assumptions of the two-compartment model

Mixing is instantaneous within each compartment, absorption and elimination occurs in the central compartment only, mixing between compartments is slow.

Two compartment model

Takes into consideration that elimination does not occur from all compartments. Hence, the drug must be distributed equally first for elimination to reach equilibrium. These means that metabolism of a drug is define by two phases - alpha and beta.

Effects on the model on calculation of Vd

• Vdc calculated from C at time=0, gives the volume of the central compartment- too low dose • Vdextrap calculated by extrapolating the slop of B-phase back to the y axis to obtain C - too high dose • Vdss calculated form C at steady state gives the sum of the volumes of both central and peripheral compartments at equilibrium - best dose